Normal Fibroblast Growth Factor 23 Research Articles

Tumor-induced osteomalacia treated with T12 tumor resection

Tumor-induced osteomalacia (TIO) is a rare form of osteomalacia caused by fibroblast growth factor-23 (FGF23)-secreting tumors. Most of these tumors are phosphaturic mesenchymal tumors (PMTs) typically involving soft tissue in the extremities and bone of the appendicular skeleton and cranium. We report the case of a 60-year-old woman with about 3 years of persistent bone pain and multiple fractures, initially diagnosed as osteoporosis, who was found to have hypophosphatemia with low 1,25-dihydroxyvitamin D and elevated alkaline phosphatase and inappropriately normal FGF23 consistent with TIO. Her symptoms improved with phosphate supplementation, vitamin D and calcitriol. 68Ga-DOTATATE imaging revealed a T12 vertebral body lesion confirmed on biopsy to be a PMT. She underwent resection of the PMT with resolution of TIO and increased bone density. This rare case of TIO secondary to a PMT of the thoracic spine highlights some of the common features of PMT-associated TIO and draws attention to PMT-associated TIO as a possible cause of unexplained persistent bone pain, a disease entity that often goes undiagnosed and untreated for years. Tumor-induced osteomalacia (TIO) is typically caused by phosphaturic mesenchymal tumors (PMTs) that are usually found in the soft tissue of the extremities and bone of the appendicular skeleton/cranium and rarely in the spine. TIO may be misdiagnosed as osteoporosis or spondyloarthritis, and the correct diagnosis is often delayed for years. However, osteoporosis, in the absence of fracture, is not associated with bone pain. The hallmark of TIO is hypophosphatemia with inappropriately normal or low 1,25-dihydroxyvitamin D and elevated or inappropriately normal fibroblast growth factor-23 (FGF23) levels. In patients with unexplained persistent bone pain, a serum phosphate should be measured. Consider PMT-associated TIO as a potential cause of unexplained persistent bone pain and hypophosphatemia. PMTs express somatostatin receptors and may be identified with 68Ga-DOTATATE imaging. Complete surgical resection is the preferred treatment for spinal PMTs associated with TIO.

Tumor-Induced Osteomalacia With Normal Fibroblast Growth Factor-23 (FGF23) and Idiopathic Hypercalciuria

Tumor-induced osteomalacia (TIO) is a rare acquired paraneoplastic syndrome characterized by low serum phosphate, phosphaturia, inappropriately low/normal levels of serum calcitriol, and normal or elevated levels of fibroblast growth factor-23 (FGF23). Finding this mesenchymal tumor is challenging since it is usually benign, small, slow-growing, and is localized in the appendicular skeleton. We report a 58-year-old male patient who arrived at the endocrinology outpatient clinic due to slowly progressive low back pain and generalized weakness since the age of 48. On physical examination, only a reduced range of motion was noted. Laboratory tests revealed hypophosphatemia with normal parathyroid hormone (PTH) levels, normal serum calcium, high 24-hour urine calcium, normal 1,25-dihydroxyvitaminD levels, low renal threshold phosphate concentration (TmPO4/GFR), and high FGF23. The 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) reported a hypermetabolic extramedullary lesion in the C1-C2 vertebral bodies measuring 1.5 x 1.1 cm. Two months after the 18F-FDG PET/CT, complete excision of the cervical tumor was performed. The pathology ward reported a histiocytic mesenchymal neoplasm with accumulations of multinucleated giant cells compatible with phosphaturic mesenchymal tumor. After surgery, the patient’s hypophosphatemia was completely resolved. With this, the diagnosis of TIO was confirmed. The patient remains asymptomatic, with normal phosphate levels at one year of follow-up. Hypophosphatemia due to renal losses in an adult patient is a challenging diagnosis and one must consider TIO, autosomal dominant hypophosphatemic rickets, fibrous dysplasia, and even Fanconi syndrome. FGF23 can be extremely useful during the diagnostic approach since acquired dependent hypophosphatemia (FGF23 ≥ 30 RU/mL) highly suggests TIO. In this case report, we want to highlight the paramount importance of adequate tumor screening in adult patients with acquired FGF23-dependent hypophosphatemia. TIO is a reversible cause of hypophosphatemia with potentially disabling consequences if left untreated. These manifestations are non-specific (bone pain and muscle weakness), while others are progressive and severely disabling (bone deformities and multiple fractures). In this case report, we want to highlight the paramount importance of adequate tumor screening in adult patients with acquired hypophosphatemia, and the crucial lead that phosphate and vitamin D regulating hormones (FGF23) have for suspecting TIO.

Correlation Between Fibroblast Growth Factor-23 and Pulmonary Arterial Hypertension in Hemodialysis Patients

Pulmonary artery hypertension (PAH) is common in end stage renal disease (ESRD) patients undergoing hemodialysis. Fibroblast growth factor-23 (FGF-23) increases in hemodialysis but its relationship with PAH is not completely understood. The aim of this study was to evaluate the relation between FGF-23 level and development of PAH in ESRD patients undergoing hemodialysis. Patients undergoing hemodialysis for more than 6 months were enrolled in this cross-sectional study. Transthoracic echocardiography was performed to measure ejection fraction and pulmonary artery pressure (PAP) in all patients. Patients were grouped into normal PAP (PAP < 25 mmHg), elevated PAP (25 < PAP < 35 mmHg) and PAH (PAP > 35 mmHg). Parathormone hormone, calcium, phosphorus, vitamin D, and hemoglobin levels were also evaluated. Eighty-five patients (48 male, 56.47%) enrolled in this study. The mean age of the patients was 51.05 ± 16.45 years. Most of the patients (49, 57.65%) had normal PAP, 20 (23.53%) had elevated PAP and 16 (18.82%) had PAH. Serum biochemical markers and demographic characteristics were not significantly related to different PAP values (P > .05). Most of the patients (42, 49.41%) had normal FGF-23 levels. There was a significant relationship between PAP groups and FGF-23 and parathormone levels, P < .001, and P < .05; respectively. FGF-23 was significantly higher in PAH and elevated PAP groups compared with normal PAP group (P < .05). Only a significant positive correlation was observed between FGF-23 levels and PAP (P < .001). This finding highlights the possible role of FGF-23 in the development of vascular complications in ESRD patients.

A Normal FGF23 Does Not Preclude Tumor-Induced Osteomalacia.

ABSTRACTTumor‐induced osteomalacia (TIO) is a rare cause of impaired bone mineralization mediated by the osteocyte‐derived, phosphaturic hormone: fibroblast growth factor 23 (FGF23). The case is presented of a previously healthy 45‐year‐old man who developed fragility fractures at multiple sites (initially metatarsals, eventually ribs, hips, spine, scapula, and sacrum) resulting in rapid functional deterioration, weakness, and the inability to bear weight and ambulate without a walker. Workup for secondary causes of bone loss was negative except for mild hypogonadotropic hypogonadism with normal pituitary MRI and hypophosphatemia that persisted despite aggressive supplementation. Testosterone was initiated but discontinued 6 months later because of deep vein thrombosis and pulmonary embolism, likely provoked by his new sedentary state, in addition to smoking history and possibly testosterone usage. Serum FGF23 was nonelevated at 138 mRU/mL (44–215). A genetic panel for OI variants was negative for a causal mutation. At the age of 48, 3 years after his initial fracture, he was referred to our academic endocrine clinic. We ruled out additional mutations that lead to hypophosphatemic rickets, including phosphate‐regulating endopeptidase homolog, X‐linked. PET/CT looking for a potential TIO locus revealed uptake in the left suprapatellar recess. Biopsy was consistent with a phosphaturic mesenchymal tumor. FGF23 was repeated for a preoperative baseline and now found to be elevated at 289 mRU/mL. In retrospect, it is likely that the initial level was inappropriately elevated for the degree of hypophosphatemia. After resection, he experienced marked improvement in physical function, decreased pain, and resolution of renal phosphate wasting. The principals of establishing a robust clinical diagnosis of TIO should be emphasized, excluding other entities and avoiding pitfalls in the interpretation of laboratory testing. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

SAT-373 A Case of X Linked Hypophosphatemic Rickets Due to DE Novo Phex Gene Mutation

IntroductionRickets is a condition that can affect bones of infants and children. It is characterized by growth plate demineralization and can occur secondary to, most commonly, vitamin D deficiency or various problems with vitamin D, Calcium or Phosphate metabolism.Hypophosphatemic rickets (HR) is a type of rickets that is inherited by X linked dominant pattern mainly however it can be also inherited by autosomal dominant and recessive patterns in rare cases. X linked dominant type (XLH) affects about 1 in 20,000 newborns. Each of the other hereditary forms of HR has been identified in only a few families.Clinical features of XLH is similar to other types of rickets including metaphyseal widening, palpable rachitic rosaries, frontal prominence, malformation of the horizontal depression along the lower border of the chest, insufficient weight gain and leg bowing.Case presentation:A 10-month-old infant presented to endocrinology with vitamin D deficiency, low serum phosphorus and hyperparathyroidism. Physical examination showed macrocephaly with frontal bossing, widening of the wrists and rachitic rosaries. His lab results showed low 25 OH vitamin D (11 ng/ml) (N:20-50 ng/ml), low phosphorus (PO4) (3.3 mg/dl) (N:4-6.5 mg/dl), high PTH (113 pg/ml) (N: 20-65pg/ml), high alkaline phosphatase (ALP) (836 IU/L) (N: 135-518 IU/L) and normal calcium (Ca2+) (9.6 mg/dl) (N:9-11 mg/dl). Vitamin D treatment was started however his follow up lab results showed persistent hypophosphatemia for age (2.8mg/dl) and elevated ALP (600IU/l) despite normalization of vitamin D (38 ng/ml). Additional lab tests were done showing high PO4 excretion (19.5 mg/dl)(N:1:3.5 mg/dl), Ca/Cr ratio 0.005 (N <0.14), inappropriately normal FGF23 level (129 RU/ml) (N: >124 RU/mL). Genetic testing showed de novo mutation in PHEX gene (871C>T) which is consistent with XLH.PHEX gene mutation is the most common mutation associated with XLH. Normally this gene can directly or indirectly regulate a protein called fibroblast growth factor 23 (produced from FGF23 gene). This protein normally inhibits renal reabsorption of phosphate into the bloodstream. Gene mutations increase the production or reduce the breakdown of fibroblast growth factor 23 leading to an overactivation of this protein and reduction of phosphate reabsorption by the kidneys, resulting in hypophosphatemia.The patient was maintained on Burosomab (0.4 mg/kg biweekly); a recombinant human monoclonal antibody (IgG1) that binds to and inhibits the activity of fibroblast growth factor 23 (FGF23) and increases the phosphate reabsorption in the renal tubules.Conclusion:XLH due to PHEX gene mutation should be considered in rachitic children who have persistently low phosphate levels despite treating vitamin D deficiency.

MON-353 Tumor-Induced Osteomalacia from a Hypervascular Thoracic Paraspinal Mass: Challenges in Diagnosis and Management

Background: Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome driven by ectopic production of fibroblast growth factor 23 (FGF23), resulting in renal phosphate wasting, hypophosphatemia, and bone demineralization. Successful therapy requires complete resection of the tumor, which is often challenging to localize. Clinical Case: A bedridden 37-year-old woman presented to Endocrine Clinic after 9 years of progressive pain and weakness in her back, hips, and extremities. She had previously been diagnosed with a neurodegenerative disease, though an MRI from 5 years ago showed bilateral subacute sacral ala fractures. CT scan on presentation showed generalized osteopenia and numerous subacute to chronic atraumatic fractures (involving ribs, scapula, pubic rami, and right femoral shaft) concerning for osteomalacia. On exam, she had profound lower extremity weakness. Laboratory testing was notable for serum phosphorus 0.6 mg/dL (normal (nl) 2.5-4.9), calcium 8.4 mg/dL (nl 8.5-10.5), PTH 216 pg/mL (nl 13-85), 25-OH vitamin D 26 ng/mL (nl 30-100), alkaline phosphatase 345 U/L (nl 45-130), 1,25-(OH)2 vitamin D 28 pg/mL (nl 18-72), renal tubular phosphorus reabsorption TmP/GFR 0.53 mg/dL (nl 2.97-4.45), and inappropriately normal FGF23 level 170 RU/mL (nl<180). Phosphate salts, calcitriol, and cinacalcet were initiated. Octreotide scan was negative, but 18F-FDG PET/CT showed mild hypermetabolic activity in the lower thoracic paraspinal area correlating with a 3.4 cm hypervascular mass near the left 8th rib head and two adjacent nodules on MRI. Due to bleeding risk, biopsy was deferred and further confirmatory studies were pursued. Genetic testing for hereditary forms of hypophosphatemia (FGF23, CLCN5, DMP1, ENPP1, FGFR1, PHEX) was negative. 68Ga-DOTATATE PET/CT was not available, but selective venous sampling for FGF23 revealed a 3:1 ratio between venous drainage of the tumor bed and general circulation. Based on this localization, surgical resection was performed. Pathology was consistent with a phosphaturic mesenchymal tumor, but clear margins could not be confirmed due to intraoperative tumor fragmentation. Three months of medical management with phosphate salts and calcitriol normalized her phosphorus levels (2.5-3.3 mg/dL), and she underwent surgical repair of her femoral fracture. Although MRI revealed only postsurgical changes in the spine, her continued requirement for phosphate supplementation and persistently elevated FGF23 levels (258 RU/mL) are concerning for residual tumor. Conclusion: This case illustrates the challenges of TIO due to a hypervascular mass in a rare paraspinal site localized by selective venous sampling for the first time at our institution. The patient’s continued FGF23 elevation underscores the importance of advancing medical therapies, such as burosumab, in patients with TIO that are not amenable to complete surgical resection.

Hyperphosphatemia with low FGF7 and normal FGF23 and sFRP4 levels in the circulation characterizes pediatric hypophosphatasia.

Hypophosphatasia (HPP) is the inborn-error-of-metabolism caused by loss-of-function mutation(s) of the ALPL gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). TNSALP in healthy individuals is on cell surfaces richly in bone, liver, and kidney. Thus, TNSALP natural substrates accumulate extracellularly in HPP, including inorganic pyrophosphate (PPi), a potent inhibitor of hydroxyapatite crystal formation and growth. Superabundance of extracellular PPi (ePPi) in HPP impairs mineralization of bones and teeth, often leading to rickets during childhood and osteomalacia in adult life and to tooth loss at any age. HPP's remarkably broad-ranging severity is largely explained by nearly four hundred typically missense mutations throughout the ALPL gene that are transmitted as an autosomal dominant or autosomal recessive trait. In the clinical laboratory, the biochemical hallmark of HPP is low serum ALP activity (hypophosphatasemia). However, our experience indicates that hyperphosphatemia from increased renal reclamation of filtered inorganic phosphate (Pi) is also common. Herein, from our prospective single-center study, we document throughout the clinical spectrum of non-lethal pediatric HPP that hyperphosphatemia reflects increased renal tubular threshold maximum for phosphorus adjusted for the glomerular filtration rate (TmP/GFR). To explore its pathogenesis, we studied mineral metabolism and quantitated circulating levels of three phosphatonins [fibroblast growth factor 23 (FGF23), secreted frizzled-related protein 4 (sFRP4), and fibroblast growth factor 7 (FGF7)] in 41 pediatric patients with HPP, 73 with X-linked hypophosphatemia (XLH), and 15 healthy pediatric control (CTR) subjects. The HPP and XLH cohorts had normal serum total and ionized calcium and parathyroid hormone levels (Ps > 0.10) and uncompromised glomerular filtration. In XLH, serum FGF23 was characteristically elevated (P < 0.0001) and despite hypophosphatemia sFRP4 was normal (P > 0.4) while FGF7 was low (P < 0.0001). In HPP, despite hyperphosphatemia serum FGF23 and sFRP4 were normal (Ps > 0.8) while FGF7 was low (P < 0.0001). Subsequently, in rats, we confirmed that FGF7 is phosphaturic. Thus, hyperphosphatemia in non-lethal pediatric HPP is associated with phosphatonin insufficiency together with, as we discuss, ePPi excess and diminished renal TNSALP activity.

Bone involvement and mineral metabolism in Williams' syndrome.

The previous studies suggested a possible increased risk of hypercalcaemia and reduced bone mineral density (BMD) in Williams' syndrome (WS). However, an extensive study regarding bone metabolism has never been performed. To investigate bone health in young adults with WS. Cross-sectional study. Endocrinology and Metabolic Diseases and Medical Genetic Units. 29 WS young adults and 29 age- and sex-matched controls. In all subjects, calcium, phosphorus, bone alkaline phosphatase (bALP), parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHVitD), osteocalcin (OC), carboxyterminal cross-linking telopeptide of type I collagen (CTX), 24-h urinary calcium and phosphorus, femoral-neck (FN) and lumbar-spine (LS) BMD and vertebral fractures (VFx) were assessed. In 19 patients, serum fibroblast growth factor-23 (FGF23) levels were measured. WS patients showed lower phosphorus (3.1 ± 0.7 vs 3.8 ± 0.5mg/dL, p = 0.0001) and TmP/GFR (0.81 ± 0.32 vs 1.06 ± 0.25mmol/L, p = 0.001), and an increased prevalence (p = 0.005) of hypophosphoremia (34.5 vs 3.4%) and reduced TmP/GFR (37.9 vs 3.4%). Moreover, bALP (26.3 ± 8.5 vs 35.0 ± 8.0U/L), PTH (24.5 ± 12.6 vs 33.7 ± 10.8pg/mL), OC (19.4 ± 5.3 vs 24.5 ± 8.7ng/mL), and FN-BMD (- 0.51 ± 0.32 vs 0.36 ± 0.32) were significantly lower (p < 0.05), while CTX significantly higher (401.2 ± 169.3 vs 322.3 ± 122.4pg/mL, p < 0.05). Serum and urinary calcium and 25OHVitD levels, LS-BMD and VFx prevalence were comparable. No cases of hypercalcemia and suppressed FGF23 were documented. Patients with low vs normal phosphorus and low vs normal TmP/GFR showed comparable FGF23 levels. FGF23 did not correlate with phosphorus and TmP/GFR values. Adult WS patients have reduced TmP/GFR, inappropriately normal FGF23 levels and an uncoupled bone turnover with low femoral BMD.

Effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism in children with chronic kidney disease.

We investigated the effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism, i.e. serum levels of fibroblast growth factor 23 (FGF23), Klotho, bone alkaline phosphatase (BAP) and sclerostin, in two cohorts with chronic kidney disease (CKD). In all, 80 vitamin D-deficient children were selected: 40 with mild to moderate CKD from the ERGO study, a randomized trial of ergocalciferol supplementation [estimated glomerular filtration rate (eGFR) 55 mL/min/1.73 m2], and 40 with advanced CKD from the observational Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study (eGFR 24 mL/min/1.73 m2). In each study, vitamin D supplementation was started in 20 children and 20 matched children not receiving vitamin D served as controls. Measures were taken at baseline and after a median period of 8 months. Age- and gender-related standard deviation scores (SDSs) were calculated. Before vitamin D supplementation, children in the ERGO study had normal FGF23 (median 0.31 SDS) and BAP (-0.10 SDS) but decreased Klotho and sclerostin (-0.77 and -1.04 SDS, respectively), whereas 4C patients had increased FGF23 (3.87 SDS), BAP (0.78 SDS) and sclerostin (0.76 SDS) but normal Klotho (-0.27 SDS) levels. Vitamin D supplementation further increased FGF23 in 4C but not in ERGO patients. Serum Klotho and sclerostin normalized with vitamin D supplementation in ERGO but remained unchanged in 4C patients. BAP levels were unchanged in all patients. In the total cohort, significant effects of vitamin D supplementation were noted for Klotho at eGFR 40-70 mL/min/1.73 m2. Vitamin D supplementation normalized Klotho and sclerostin in children with mild to moderate CKD but further increased FGF23 in advanced CKD.

Investigating FGF-23 concentrations and its relationship with declining renal function in paediatric patients with pre-dialysis CKD Stages 3-5

The aims of our study were to investigate (i) the prevalence of elevated fibroblast growth factor-23 (FGF-23), (ii) the relationship between FGF-23 concentrations and level of renal dysfunction and (iii) the main determinants of elevation of FGF-23 concentration in children with pre-dialysis chronic kidney disease (CKD) Stages 3-5. In this single-centre prospective observational study, 71 children with pre-dialysis CKD Stages 3-5, aged 11.9 ± 3.1 years, had FGF-23 levels measured. Anthropometry and routine laboratory investigations were measured. Fourteen (19.7%) patients had normal FGF-23 concentrations defined as < 50 ng/L. FGF-23 [median (interquartile range)] concentrations were 78.7 (55.6-137.6) ng/L and following log transformation normalized data with log FGF-23 [mean (SD)] values of 1.96 ± 0.4 ng/L. Log FGF-23 concentrations had a negative reciprocal relationship with estimated glomerular filtration rate (eGFR) (P < 0.0001) and 1,25 vitamin D3 levels (P = 0.01) and a positive relationship with phosphate (P = 0.03) and percent fractional excretion of phosphate (P = 0.01) but not with log-intact parathyroid hormone (PTH) (P = 0.22). Multiple linear regression demonstrated a strong relationship between log FGF-23 and eGFR only. Elevated FGF-23 concentrations were observed in the majority of a carefully managed cohort of children with non-dialysis CKD with a dominant effect on FGF-23 concentrations with glomerular filtration rate (GFR). These data allow the potential confounding effects of PTH and phosphate elevation with declining GFR to be removed, leaving a clearer picture of the FGF-23-GFR relationship.

Soluble klotho and autosomal dominant polycystic kidney disease.

Fibroblast growth factor 23 (FGF23) levels are elevated in patients with autosomal dominant polycystic kidney disease (ADPKD) and X-linked hypophosphatemia (XLH), but only the latter is characterized by a renal phosphate wasting phenotype. This study explored potential mechanisms underlying resistance to FGF23 in ADPKD. FGF23 and klotho levels were measured, and renal phosphate transport was evaluated by calculating the ratio of the maximum rate of tubular phosphate reabsorption to GFR (TmP/GFR) in 99 ADPKD patients, 32 CKD patients, 12 XLH patients, and 20 healthy volunteers. ADPKD and CKD patients were classified by estimated GFR (CKD stage 1, ≥90 ml/min per 1.73 m(2); CKD stage 2, 60-89 ml/min per 1.73 m(2)). ADPKD patients had 50% higher FGF23 levels than did XLH patients; TmP/GFR was near normal in most ADPKD patients and very low in XLH patients. Serum klotho levels were lowest in the ADPKD group, whereas the CKD and XLH groups and volunteers had similar levels. ADPKD patients with an apparent renal phosphate leak had two-fold higher klotho levels than those without. Serum klotho values correlated inversely with cyst volume and kidney growth. Loss of klotho might be a consequence of cyst growth and constrain the phosphaturic effect of FGF23 in most patients with ADPKD. Normal serum klotho levels were associated with normal FGF23 biologic activity in all XLH patients and a minority of ADPKD patients. Loss of klotho and FGF23 increase appear to exceed and precede the changes that can be explained by loss of GFR in patients with ADPKD.

Normal FGF23 Levels in Adult Idiopathic Phosphate Diabetes

Fibroblast growth factor 23 (FGF23), a recently discovered phosphaturic substance playing a key role in genetic and oncogenic phosphate diabetes, is involved in the physiological regulation of phosphate metabolism. Moderate idiopathic phosphate diabetes (IPD) leading to male osteoporosis and diffuse pain resembling fibromyalgia has been described. The aim of our study was to define the role of FGF23 in the mechanism of IPD. The study concerned 29 patients with IPD, mean age 53 +/- 11 years, of whom 72% were men. Fifteen subjects without bone disease and with normal serum phosphate and calcium levels were used as controls. Phosphate diabetes was confirmed by phosphate reabsorption level <85% and phosphate reabsorption threshold (TmPO4/GFR) <0.83. Known causes of phosphate diabetes were excluded. Fasting level of FGF23, serum phosphate, 1-25(OH)2D3, and parathyroid hormone were measured in patients and compared with FGF23 and serum phosphate in healthy controls. Spinal and hip bone mineral density (BMD) were measured by osteodensitometry. Sixteen of 29 patients had diffuse pain, 10 had osteoporosis according to the World Health Organization criteria, and 11 had osteopenia. Serum phosphate was significantly lower in patients than in controls, but FGF23 levels did not differ. Compared to patients with normal bone status, patients with osteopenia and osteoporosis had significantly decreased FGF23 levels, whereas serum phosphate was identical in the two groups. In all patients, serum phosphate and FGF23 were positively correlated and FGF23 and 1-25(OH)2D3 were negatively correlated. FGF23 seems not be a cause of IPD, and the FGF23/phosphate/1-25(OH)2D3 axis appeared to be functional.

Sensitivity of Fibroblast Growth Factor 23 Measurements in Tumor-Induced Osteomalacia

Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome of hypophosphatemia, decreased renal phosphate reabsorption, normal or low serum 1,25-dihydryxyvitamin-D concentration, myopathy, and osteomalacia. Fibroblast growth factor 23 (FGF23) is a phosphaturic protein overexpressed in tumors that cause TIO and is, at least partly, responsible for the manifestations of TIO. The objective of this study was to determine the sensitivity of FGF23 measurements in TIO. FGF23 concentrations were measured on stored samples with three ELISAs. This study was conducted at subspecialty referral centers. Twenty-two patients with suspected TIO, 13 with confirmed tumors, were studied. There were no interventions in this study. FGF23 concentration was the main outcome measure of this study. Elevated FGF23 concentrations were detected using the Immunotopics C-terminal assay in 16 of 22 TIO patients (for a sensitivity of 73%), the Immunotopics Intact assay in five of 22 patients (sensitivity, 23%), and the Kainos Intact assay in 19 of 22 patients (sensitivity, 86%). In the 13 patients with confirmed tumors, the sensitivity was higher with all assays: 92% for the Immunotopics C-terminal assay, 38% for the Immunotopics Intact assay, and 100% for the Kainos assay. The Kainos Intact assay was the most sensitive, followed by the Immunotopics C-terminal assay. The findings of normal FGF23 concentrations in some patients with TIO may indicate that FGF 23 is not responsible for the hypophosphatemia in these patients or that FGF23 secretion by some tumors is partially responsive to serum phosphate. Normal FGF23 concentrations should be interpreted in relation to the serum phosphate and 1,25-dihydryxyvitamin-D concentrations.