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Year : 2022  |  Volume : 10  |  Issue : 1  |  Page : 39-41

Tumor-induced osteomalacia: Easing the diagnosis with fibroblast growth factor 23

Department of Endocrinology, Ramaiah Medical College, Bengaluru, Karnataka, India

Date of Submission13-May-2020
Date of Decision06-Jun-2020
Date of Acceptance07-Jul-2020
Date of Web Publication06-Jan-2022

Correspondence Address:
Dr. Mala Dharmalingam
Department of Endocrinology, Ramaiah Medical College, Mathikere, New BEL Road, Bengaluru - 560 054, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/AJIM.AJIM_35_20

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Tumor-induced osteomalacia (TIO), is a rare paraneoplastic syndrome resulting in bone pain, muscle weakness, and recurrent fractures. Hypophosphatemia, hyperphosphaturia, low 1, 25 dihydroxyVitamin D, and normal serum calcium are noted. It is mostly caused by fibroblast growth factor 23 (FGF23) secreting tumors. Apart from testing for FGF23, additional imaging modalities are required to identify the causative lesion. Prompt remission follows successful lesion excision. This case report highlights the importance of FGF 23 in the diagnosis of TIO.

Keywords: DOTANOC positron emission tomography, fibroblast growth factor 23, osteomalacia, phosphorous

How to cite this article:
Dharmalingam M, Kumbar L. Tumor-induced osteomalacia: Easing the diagnosis with fibroblast growth factor 23. APIK J Int Med 2022;10:39-41

How to cite this URL:
Dharmalingam M, Kumbar L. Tumor-induced osteomalacia: Easing the diagnosis with fibroblast growth factor 23. APIK J Int Med [serial online] 2022 [cited 2022 Aug 11];10:39-41. Available from: https://www.ajim.in/text.asp?2022/10/1/39/335082

  Introduction Top

Osteomalacia is Vitamin D deficiency presenting in adults. There are different etiologies of osteomalacia, one of it being tumor-induced osteomalacia (TIO). TIO, also known as oncogenic osteomalacia, is a rare paraneoplastic syndrome characterized by bone pain, muscle weakness, and fractures associated with persistent hypophosphatemia. TIO is caused by tumoral overproduction of fibroblast growth factor 23 (FGF23), which inhibits renal proximal tubule phosphate reabsorption and 1α-hydroxylation of 25-hydroxyvitamin D, leading to hypophosphatemia and ultimately osteomalacia.[1],[2]

Once the tumor has been localized, successful removal of the tumor causing TIO will result in a reversal of biochemical abnormalities.[3]

  Case Report Top

A 36-year male came with complaints of bilateral hip pain for the past 3 years and inability to stand due to pain and had become bedridden due to proximal muscle weakness and pain.

He was apparently normal 3 years back when he had a trivial fall from the bed. He was evaluated and found to have a hairline fracture in the pubic rami and was advised bed rest along with analgesics. The patient was alright for about 3 months; however, his symptoms recurred and this time, he was evaluated extensively [Table 1]. The patient was evaluated with magnetic resonance imaging of the hip and found to have multiple hairline fractures in the pelvic bone. The patient was planned for the surgery for fixation of fracture but was deferred in view of fragile bone.
Table 1: Investigations at baseline

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As phosphorous was very low, he was suspected of osteomalacia and had a fluorodeoxyglucose positron emission tomography (PET) scan of the whole body; however, no tumor was detected. The patient was prescribed calcium supplements along with Vitamin D supplements. The patient became bedridden and was unable to walk.

The patient came to our center and his initial evaluation revealed very low phosphorous, normal calcium, and Vitamin D levels. The TmP glomerular filtration rate was low, and FGF 23 was high [Table 2]. The patient was started on phosphate replacement.
Table 2: Specialised work up

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A Ga68 DOTANOC PET scan was done, which revealed a 1.8 cm × 1.4 cm enhancing somatostatin receptor avid periapical soft tissue in the right anterior maxillary alveolus, likely representing of hemangiopericytoma/oncogenic osteomalacic focus [Figure 1].
Figure 1: 68Ga DOTANOC positron emission tomography scan showing the lesion in maxilla (a) with contrast (b) without contrast (Arrow pointing out the lesion)

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The patient underwent excision of the tumor, and histopathology showed ameloblastoma, involving maxilla and palatal bone. Phosphate supplements were stopped, and repeat serum phosphorous started normalizing. The patient symptomatically improved. FGF 23 was repeated, which was 38.5 RU/ml [Table 3]. The patient was seen 6 months later and could walk on his own without support.
Table 3: Laboratory values before and after surgery

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  Discussion Top

Tumor-induced osteomalacia, a rare paraneoplastic disorder, is caused by tumors secreting FGF23, leading to hypophosphatemia and ultimately resulting in osteomalacia. The diagnosis of TIO is usually suspected when serum phosphate levels are persistently low in the setting of bone pain, fragility fractures, and muscle weakness.[2]

FGF23 is usually secreted by benign and rarely malignant mesenchymal tumors.[4] FGF23 is produced by osteoblasts, osteocytes, and erythroid precursor cells.[5] The active hormone which is physiologically secreted is as an intact, full-length 251-amino acid protein, which is O-glycosylated by polypeptide N-acteylgalatosaminyltransferase 3. FGF23 action is mediated by binding to its receptor, fibroblast growth factor receptor 1, and coreceptor α-Klotho.

FGF23 downregulates the sodium phosphate cotransporters NaPi-2a and NaPi-2c by decreasing proximal tubule phosphate reabsorption and causing phosphaturia. It also suppresses 1-alpha-hydroxylation and thus active Vitamin D, further reducing phosphate absorption in the intestine.[5]

Measurement of FGF23 can be done by commercially available four immunoassays: Immutopics (1st and 2nd generation, San Clemente, California, USA), Kainos (Tokyo, Japan), Millipore (Billerica, Massachusetts, USA), and DiaSorin (Saluggia, Italy). Most assays will measure the intact 251 amino-acid protein (iFGF23). Immutopics have the advantage of measuring both iFGF23 and the C-terminal fragment of FGF23 (cFGF23).[6] In our patient, the test was done by the ELISA method. It is preferable when measuring iFGF23 to use fasting samples or early morning samples.[7]

The 95% reference limits of plasma iFGF23 in healthy adults is 11.7–48.6 pg/ml and for cFGF23 21.6–91.0 RU/ml. The intra- and inter-assay coefficient of variation are respectively, <2.4% and <4.7% for the second-generation Immutopics cFGF23, <9.7% and <14% for the Kainos assay, <2.9% and <6.3% for the DiaSorin assay, and <10% and <8% for the Millipore assay.[6]

The initial step in the diagnosis is by functional imaging followed by anatomical imaging.[2] 68Ga-DOTATATE has a higher affinity for Type 2 and Type 5 somatostatin receptors than does pentetreotide, and it is has been shown that DOTA-based nuclear studies may be superior to those using octreoscan-based imaging.[8]

The mainstay of therapy for TIO is complete surgical resection of the tumor.[9]

When the tumor causing TIO is localized and successfully removed, there is a reversal of the biochemical abnormalities. With a short half-life of 46–58 min, circulating levels of FGF23 decrease rapidly with improvement in patients' symptoms within days or weeks, but the improvement of the skeletal disease may take up to a year.[3]

When tumor cannot be located by imaging or complete resection is not possible, medical treatment is necessary, which includes phosphate and Vitamin D supplements. The goals of treatment are to increase serum phosphate levels to lower end of the normal range, improve symptoms and normalize serum alkaline phosphatase levels.[2]

The role of adjuvant radiotherapy to prevent recurrence is limited in cases where surgery is incomplete.[3] The use of different techniques, including percutaneous ethanol ablation, radiofrequency ablation, and cryoablation, offer an alternative approach in inoperable TIO.[10]

  Conclusion Top

TIO is a completely correctable bone condition. A high degree of suspicion, proper evaluation, and management can prevent affected persons from getting physically handicapped. An early diagnosis with the use of FGF23 and management with surgical resection is mandated. When the tumor is not resectable medical treatment with phosphate supplements or radiotherapy is the treatment of choice.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Chong WH, Molinolo AA, Chen CC, Collins MT. Tumor-induced osteomalacia. Endocr Relat Cancer 2011;18:R53-77.  Back to cited text no. 1
Minisola S, Peacock M, Fukumoto S, Cipriani C, Pepe J, Tella SH, et al. Tumour-induced osteomalacia. Nat Rev Dis Primers 2017;3:17044.  Back to cited text no. 2
Dadoniene J, Miglinas M, Miltiniene D, Vajauskas D, Seinin D, Butenas P, et al. Tumour-induced osteomalacia: A literature review and a case report. World J Surg Oncol 2016;14:4.  Back to cited text no. 3
Chanukya GV, Mengade M, Goud J, Rao IS, Jain A. Tumor-induced osteomalacia: A Sherlock Holmes approach to diagnosis and management. Ann Maxillofac Surg 2017;7:143-7.  Back to cited text no. 4
[PUBMED]  [Full text]  
Florenzano P, Hartley IR, Jimenez M, Roszko K, Gafni RI, Collins MT. Tumor-Induced Osteomalacia. Calcif Tissue Int 2020. doi: 10.1007/s00223-020-00691-6.  Back to cited text no. 5
Bouma-de Krijger A, Vervloet MG. Fibroblast growth factor 23: Are we ready to use it in clinical practice? J Nephrol 2020;33:509-27.  Back to cited text no. 6
Smith ER, Cai MM, McMahon LP, Holt SG. Biological variability of plasma intact and C-terminal FGF23 measurements. J Clin Endocrinol Metab 2012;97:3357-65.  Back to cited text no. 7
El-Maouche D, Sadowski SM, Papadakis GZ, Guthrie L, Cottle-Delisle C, Merkel R, et al. 68Ga-DOTATATE for tumor localization in tumor-induced osteomalacia. J Clin Endocrinol Metab 2016;101:3575-81.  Back to cited text no. 8
Zuo QY, Wang H, Li W, Niu XH, Huang YH, Chen J, et al. Treatment and outcomes of tumor-induced osteomalacia associated with phosphaturic mesenchymal tumors: Retrospective review of 12 patients. BMC Musculoskelet Disord 2017;18:403.  Back to cited text no. 9
Pal R, Bhadada SK, Singhare A, Bhansali A, Kamalanathan S, Chadha M, et al. Tumor-induced osteomalacia: Experience from three tertiary care centers in India. Endocr Connect 2019;8:266-76.  Back to cited text no. 10


  [Figure 1]

  [Table 1], [Table 2], [Table 3]


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