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      Tumor-induced osteomalacia: experience from three tertiary care centers in India


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          Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by recalcitrant hypophosphatemia. Reports from the Indian subcontinent are scarce, with most being single center experiences involving few patients. Herein, we conducted a retrospective analysis of 30 patients of TIO diagnosed at three tertiary care hospitals in India. Patients with persistent hypophosphatemia (despite correction of hypovitaminosis D), normocalcemia, elevated alkaline phosphatase, low TmP/GFR and elevated or ‘inappropriately normal’ FGF23 levels were labeled as having TIO. They were sequentially subjected to functional followed by anatomical imaging. Patients with a well-localized tumor underwent excision; others were put on phosphorous and calcitriol supplementation. The mean age at presentation was 39.6 years with female:male ratio of 3:2. Bone pain (83.3%) and proximal myopathy (70%) were the chief complaints; 40% of cases had fractures. The mean delay in diagnosis was 3.8 years. Tumors were clinically detectable in four patients (13.3%). The mean serum phosphate was 0.50 mmol/L with a median serum FGF23 level of 518 RU/mL. Somatostatin receptor-based scintigraphy was found to be superior to FDG-PET in tumor localization. Lower extremities were the most common site of the tumor (72%). Tumor size was positively correlated with serum FGF23 levels. Twenty-two patients underwent tumor resection and 16 of them had phosphaturic mesenchymal tumors. Surgical excision led to cure in 72.7% of patients whereas disease persistence and disease recurrence were seen in 18.2% and 9.1% of cases, respectively. At the last follow-up, serum phosphate in the surgically treated group was significantly higher than in the medically managed group.

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          Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia.

          Mutations in fibroblast growth factor 23 (FGF-23) cause autosomal dominant hypophosphatemic rickets. Clinical and laboratory findings in this disorder are similar to those in oncogenic osteomalacia, in which tumors abundantly express FGF-23 messenger RNA, and to those in X-linked hypophosphatemia, which is caused by inactivating mutations in a phosphate-regulating endopeptidase called PHEX. Recombinant FGF-23 induces phosphaturia and hypophosphatemia in vivo, suggesting that it has a role in phosphate regulation. To determine whether FGF-23 circulates in healthy persons and whether it is elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, an immunometric assay was developed to measure it. Using affinity-purified, polyclonal antibodies against [Tyr223]FGF-23(206-222)amide and [Tyr224]FGF-23(225-244)amide, we developed a two-site enzyme-linked immunosorbent assay that detects equivalently recombinant human FGF-23, the mutant form in which glutamine is substituted for arginine at position 179 (R179Q), and synthetic human FGF-23(207-244)amide. Plasma or serum samples from 147 healthy adults (mean [+/-SD] age, 48.4+/-19.6 years) and 26 healthy children (mean age, 10.9+/-5.5 years) and from 17 patients with oncogenic osteomalacia (mean age, 43.0+/-13.3 years) and 21 patients with X-linked hypophosphatemia (mean age, 34.9+/-17.2 years) were studied. Mean FGF-23 concentrations in the healthy adults and children were 55+/-50 and 69+/-36 reference units (RU) per milliliter, respectively. Four patients with oncogenic osteomalacia had concentrations ranging from 426 to 7970 RU per milliliter, which normalized after tumor resection. FGF-23 concentrations were 481+/-528 RU per milliliter in those with suspected oncogenic osteomalacia and 353+/-510 RU per milliliter (range, 31 to 2335) in those with X-linked hypophosphatemia. FGF-23 is readily detectable in the plasma or serum of healthy persons and can be markedly elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, suggesting that this growth factor has a role in phosphate homeostasis. FGF-23 measurements might improve the management of phosphate-wasting disorders. Copyright 2003 Massachusetts Medical Society
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            Tumor-induced osteomalacia.

            Tumor-induced osteomalacia (TIO) is a rare and fascinating paraneoplastic syndrome in which patients present with bone pain, fractures, and muscle weakness. The cause is high blood levels of the recently identified phosphate and vitamin D-regulating hormone, fibroblast growth factor 23 (FGF23). In TIO, FGF23 is secreted by mesenchymal tumors that are usually benign, but are typically very small and difficult to locate. FGF23 acts primarily at the renal tubule and impairs phosphate reabsorption and 1α-hydroxylation of 25-hydroxyvitamin D, leading to hypophosphatemia and low levels of 1,25-dihydroxy vitamin D. A step-wise approach utilizing functional imaging (F-18 fluorodeoxyglucose positron emission tomography and octreotide scintigraphy) followed by anatomical imaging (computed tomography and/or magnetic resonance imaging), and, if needed, selective venous sampling with measurement of FGF23 is usually successful in locating the tumors. For tumors that cannot be located, medical treatment with phosphate supplements and active vitamin D (calcitriol or alphacalcidiol) is usually successful; however, the medical regimen can be cumbersome and associated with complications. This review summarizes the current understanding of the pathophysiology of the disease and provides guidance in evaluating and treating these patients. Novel imaging modalities and medical treatments, which hold promise for the future, are also reviewed.
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              Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women.

              FGF-23 is a novel regulator of phosphate metabolism. We studied the regulation of FGF-23 by dietary phosphate in 66 men and women using two assays. Dietary phosphate restriction decreased FGF-23 and loading increased FGF-23 significantly. An assay that measured intact FGF-23 showed the effects of dietary phosphate much more clearly than an assay that also measures presumed biologically inactive fragments. Dietary phosphate is a key regulator of circulating FGF-23; choice of assay is critical when studying FGF-23 physiology. Fibroblast growth factor 23 (FGF-23) is a novel phosphaturic factor discovered through genetic studies of patients with renal phosphate wasting disorders. Ablation of the FGF-23 gene in mice reduces renal phosphate excretion and increases serum phosphate, suggesting that FGF-23 is critical for normal phosphate homeostasis. We examined the role of dietary phosphate in the regulation of FGF-23 in humans. Sixty-six healthy males and females were randomized to either phosphate-depleted or -loaded diets for 5 days, after a 4-day run-in diet. FGF-23 was measured using an "intact" assay that only detects intact FGF-23 peptide and with a "C-terminal" assay that measures both intact FGF-23 peptide and presumed biologically inactive carboxyl terminal fragments. The main outcome was the within group change in FGF-23 with either phosphate depletion or loading. Using the intact FGF-23 assay, mean FGF-23 area under the curve (AUC) decreased by 9 +/- 16% with phosphate depletion (p = 0.0041) and increased by 35 +/- 29% with loading (p < 0.0001). Using the C-terminal FGF-23 assay, mean FGF-23 AUC decreased by 8 +/- 12% with phosphate depletion (p = 0.0003) and increased by 13 +/- 20% with loading (p = 0.0016). Increases in FGF-23 with phosphate loading were greater with the intact assay than with the C-terminal assay (p = 0.0003). Using the intact assay only, FGF-23 was significantly associated with serum phosphate (r = 0.39, p < 0.01), 24-h urinary phosphate (r = 0.47, p < 0.01), fractional excretion of phosphate (r = 0.29, p < 0.01), and 1,25-dihydroxyvitamin D (r = -0.30, p < 0.01). The association between the assays was weak (r = 0.26, p < 0.01). Dietary phosphate is a key regulator of circulating FGF-23 levels in humans. Additionally, choice of assay is critical when performing physiologic investigations of FGF-23.

                Author and article information

                Endocr Connect
                Endocr Connect
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                March 2019
                28 January 2019
                : 8
                : 3
                : 266-276
                [1 ]Department of Endocrinology , Post Graduate Institute of Medical Education and Research, Chandigarh, India
                [2 ]Department of Endocrinology , P D Hinduja Hospital and Medical Research Centre, Mumbai, India
                [3 ]Department of Endocrinology , Jawaharlal Institute of Post Graduate Medical Education and Research, Pondicherry, India
                [4 ]Department of Nuclear Medicine , Post Graduate Institute of Medical Education and Research, Chandigarh, India
                [5 ]Division of Endocrinology , Rabindranath Tagore Medical College, Udaipur, India
                [6 ]Department of Histopathology , Post Graduate Institute of Medical Education and Research, Chandigarh, India
                [7 ]Department of Orthopaedics , P D Hinduja Hospital and Medical Research Centre, Mumbai, India
                Author notes
                Correspondence should be addressed to S K Bhadada: bhadadask@ 123456rediffmail.com
                © 2019 The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

                : 24 January 2019
                : 28 January 2019

                tumor-induced osteomalacia,fgf23,hypophosphatemia,phosphaturic mesenchymal tumor


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