Clinical usefulness of measurement of fibroblast growth factor 23 (FGF23) in hypophosphatemic patients: Proposal of diagnostic criteria using FGF23 measurement

doi:10.1016/j.bone.2008.02.014

Bone

Volume 42, Issue 6, June 2008, Pages 1235-1239

https://doi.org/10.1016/j.bone.2008.02.014 Get rights and content

Abstract

Fibroblast growth factor 23 (FGF23) plays important roles in the development of hypophosphatemic diseases such as tumor-induced osteomalacia (TIO) and X-linked hypophosphatemic rickets/osteomalacia (XLH). However, clinical usefulness of measurement of FGF23 has not been established. The objective of this study is to examine the importance of FGF23 measurement in the diagnosis of hypophosphatemic diseases. Biochemical parameters concerning phosphate metabolism were analyzed in a cross-sectional study. 32 patients with TIO, 28 patients with XLH and 16 hypophosphatemic patients with other causes including vitamin D deficiency, Fanconi's syndrome and Cushing's syndrome were studied. In patients with TIO and XLH, FGF23 was above the upper limit of the reference range in most patients irrespective of medical treatment. The lowest FGF23 in these patients was 38.0 pg/ml. FGF23 in hypophosphatemic patients with other causes was undetectable (less than 3 pg/ml) in 12 patients and the highest FGF23 in this group was 23.9 pg/ml. Relationship between phosphate and FGF23 indicated that TIO and XLH are diseases with high FGF23 and hypophosphatemia judged by age-dependent reference ranges for serum phosphate. FGF23 measurement is useful for differential diagnosis of hypophosphatemic diseases caused by excess actions of FGF23 and other etiologies. High FGF23 with low phosphate judged by age-dependent reference ranges for phosphate establishes the diagnosis of diseases caused by excess actions of FGF23.

Introduction

Fibroblast growth factor 23 (FGF23) is the latest member of FGF family. It has been shown that FGF23 reduces serum phosphate by inhibiting proximal tubular phosphate reabsorption and decreasing serum 1,25-dihydroxyvitamin D [1,25(OH)₂D] level [1]. FGF23 has been postulated to participate in the development of several hypophosphatemic diseases including X-linked hypophosphatemic rickets/osteomalacia (XLH) [2], [3], autosomal dominant and recessive hypophosphatemic rickets/osteomalacia (ADHR and ARHR) [4], [5], [6], tumor-induced rickets/osteomalacia (TIO) [7] and hypophosphatemia associated with McCune–Albright syndrome/fibrous dysplasia [8]. Actually, circulatory FGF23 levels were shown to be elevated in some, but not all patients with these hypophosphatemic diseases [2], [3]. There are several assay methods for measurement of FGF23. One of the reasons why some patients with these hypophosphatemic diseases show FGF23 levels within the reference range would be the difference of assay methods employed as pointed out previously [9], [10]. Another possible reason is the contribution of other confounding factors including age of patients and effects of treatment. Therefore, the clinical usefulness of measurement of FGF23 in the diagnosis of these hypophosphatemic diseases has not been established. Furthermore, the significance of FGF23 measurement in the differential diagnosis of various hypophosphatemic diseases has not been examined. The present study was undertaken to clarify the following questions. First, can FGF23 measurement establish the diagnosis of XLH or TIO considering confounding factors? Second, can FGF23 levels discriminate diseases caused by excess actions of FGF23 and other hypophosphatemic diseases? Our cross-sectional study indicates that serum phosphate level judged from age-dependent reference ranges and FGF23 levels can establish the diagnosis of XLH or TIO irrespective of the treatment for these diseases. In addition, FGF23 levels can discriminate diseases caused by excess actions of FGF23 and other hypophosphatemic diseases. FGF23 measurement seems to be clinically useful for the differential diagnosis of hypophosphatemic diseases.

Section snippets

Patients

XLH and TIO are relatively rare diseases and it is difficult to collect enough number of clinical samples in one institution. Therefore, we sent a questionnaire to members of a research group supported by the Ministry of Health, Labour and Welfare of Japan to enroll hypophosphatemic patients. After written informed consent was obtained, clinical data of these patients were collected. The diagnosis of XLH and TIO was established clinically by each member of the research group. Characteristics of

Results

Biochemical parameters in patients with TIO are shown in Fig. 1a. Serum phosphate was 1.67 +/− 0.08 mg/dl in 32 patients with TIO and was clearly low. When these patients were divided into 16 patients without and other 16 patients with medical treatment, there was no significant difference in serum phosphate levels in these two groups (1.59 +/− 0.09 mg/dl and 1.74 +/− 0.12 mg/dl, respectively). TmP/GFR in these patients was 1.24 +/− 0.08 mg/dl and was also severely suppressed. Again, there was no

Discussion

Our results confirm that TIO and XLH are characterized by impaired tubular reabsorption of phosphate and relatively low serum 1,25(OH)₂D levels for hypophosphatemia. Serum phosphate and TmP/GFR in patients treated with active vitamin D₃ and/or phosphate were not higher than those in patients without medical treatment. Although our study is a cross-sectional one, these results indicate that current medical treatment of these diseases does not correct the underlying disorder of phosphate

Acknowledgments

We thank the following Drs. for giving us opportunities to evaluate their patients. Drs. Masatomo Mori, Hisao Seo, Hirotoshi Nakamura, Takashi Akamizu, Toyoshi Endo, Kazumichi Onigata, Yuji Hiromatsu, Toshihiro Tajima, Akinobu Nakamura, Kenji Fujieda, Kumihiro Matsuo, Kousuke Iba, Takeshi Hoshikawa, Kounosuke Nakayama, Toshiyuki Yasuda, Ryo Okazaki, Nobuaki Ito, Toshiro Fujita, Makoto Takahashi, Atsuhiro Ichihara, Kanji Sato, Hiroyuki Sakai, Yukihiro Hasegawa, Yasuhiro Takeuchi, Toshiro

References (20)

R.J. Walton et al.
Nomogram for derivation of renal threshold phosphate concentration
Lancet
(1975)
H. Saito et al.
Circulating FGF-23 is regulated by 1alpha,25-dihydroxyvitamin D3 and phosphorus in vivo
J Biol Chem
(2005)
T. Shimada et al.
FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis
J Bone Miner Res
(2004)
Y. Yamazaki et al.
Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia
J Clin Endocrinol Metab
(2002)
K.B. Jonsson et al.
Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia
N Engl J Med
(2003)
ADHR consortium
Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23
Nat Genet
(2000)
J.Q. Feng et al.
Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism
Nat Genet
(2006)
B. Lorenz-Depiereux et al.
DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis
Nat Genet
(2006)
T. Shimada et al.
Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia
Proc Natl Acad Sci U S A
(2001)
M. Riminucci et al.
FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting
J Clin Invest
(2003)

There are more references available in the full text version of this article.

Cited by (167)

Complex intrinsic abnormalities in osteoblast lineage cells of X-linked hypophosphatemia: Analysis of human iPS cell models generated by CRISPR/Cas9-mediated gene ablation
2024, Bone
X-linked hypophosphatemia (XLH) is caused by inactivating variants of the phosphate regulating endopeptidase homolog X-linked (PHEX) gene. Although the overproduction of fibroblast growth factor 23 (FGF23) is responsible for hypophosphatemia and impaired vitamin D metabolism, the pathogenesis of XLH remains unclear. We herein generated PHEX-knockout (KO) human induced pluripotent stem (iPS) cells by applying CRISPR/Cas9-mediated gene ablation to an iPS clone derived from a healthy male, and analyzed PHEX-KO iPS cells with deletions extending from exons 1 to 3 and frameshifts by inducing them to differentiate into the osteoblast lineage. We confirmed the increased production of FGF23 in osteoblast lineage cells differentiated from PHEX-KO iPS cells. In vitro mineralization was enhanced in osteoblast lineage cells from PHEX-KO iPS cells than in those from isogenic control iPS cells, which reminded us of high bone mineral density and enthesopathy in patients with XLH. The extracellular level of pyrophosphate (PPi), an inhibitor of mineralization, was elevated, and this increase appeared to be partly due to the reduced activity of tissue non-specific alkaline phosphatase (TNSALP). Osteoblast lineage cells derived from PHEX-KO iPS cells also showed the increased expression of multiple molecules such as dentine matrix protein 1, osteopontin, RUNX2, FGF receptor 1 and early growth response 1. This gene dysregulation was similar to that in the osteoblasts/osteocytes of Phex-deficient Hyp mice, suggesting that common pathogenic mechanisms are shared between human XLH and Hyp mice. Moreover, we found that the phosphorylation of CREB was markedly enhanced in osteoblast lineage cells derived from PHEX-KO iPS cells, which appeared to be associated with the up-regulation of the parathyroid hormone related protein gene. PHEX deficiency also affected the response of the ALPL gene encoding TNSALP to extracellular Pi. Collectively, these results indicate that complex intrinsic abnormalities in osteoblasts/osteocytes underlie the pathogenesis of human XLH.
Clinical performance of a new intact FGF23 immunoassay in healthy individuals and patients with chronic hypophosphatemia
2023, Bone Reports
While the positive association between automated intact fibroblast growth factor (FGF) 23 measurement kit (Determinar CL FGF23 [CL]) and the former assay (Kainos [KI]), and clinical utility of CL was well established, the clinical performance of Medfrontier FGF23 (MED), which was the manual intact FGF23 measurement kit with same antibody set as CL, has not yet been validated. Therefore, this study aims to compare MED FGF23 levels to KI FGF23 levels. A total of 380 samples were collected from healthy individuals, and 200 samples were collected from 20 patients with chronic hypophosphatemia. The intact FGF23 level of each sample was measured by KI and MED. Among the healthy individuals, the reference range of MED FGF23 levels was 18.6–59.8 pg/mL when calculated as the average ± 2 standard deviations. When compared with KI FGF23 levels, MED FGF23 levels were lower than KI levels both among samples from healthy individuals (KI FGF23, 40.9 [interquartile (IQR), 31.1–50.6]; MED FGF23, 38.0 [IQR, 31.5–45.7]; p value = 0.02) and among samples from patients with chronic hypophosphatemia (KI FGF23, 172.5 [IQR, 115.8–290.7]; MED FGF23, 130.2 [IQR, 93.6–247.0]; p value = 0.003). The linear regression analysis showed that the correlation between KI FGF23 and MED FGF23 was interpreted as a slope of 0.83 with a y-intercept of 0.53, revealing good linearity (R² = 0.99). This study showed that the discrepancy between KI and MED was very similar to the previously reported data between KI and CL.
Recent basic and clinical findings concerning FGF23: A bone-derived hormone
2023, Current Opinion in Endocrine and Metabolic Research
FGF23 is essential for the regulation of serum phosphate level and the aberrant actions of FGF23 cause hypophosphatemic or hyperphosphatemic diseases. The objective of this review is to provide a current and relevant summary of the recent basic and clinical findings concerning FGF23. Recent findings: Many factors have been shown to affect FGF23 production while the precise roles of these factors in phosphate metabolism are largely unknown. Anti-FGF23 antibody has become clinically available, and the efficacy of this antibody has been reported in several hypophosphatemic diseases caused by excessive actions of FGF23.Summary: The identification of FGF23 came to the development of a new therapy for hypophosphatemic diseases. Still, there are many unanswered questions concerning FGF23.
Intact Fibroblast Growth Factor 23 Concentrations in Hypophosphatemic Disorders: Measurement of Intact FGF23
2023, Endocrine Practice
Evaluation of circulating fibroblast growth factor 23 (FGF23) concentrations plays a key role in the differential diagnosis of patients presenting with hypophosphatemia. FGF23 concentrations obtained by different immunoassays are not comparable and subsequently, differences in the clinical performance of the assays might arise. In this study, we evaluated the clinical performance of the Medfrontier FGF23 Intact immunoassay (MedFrontier, Minaris Medical Co, Ltd, Tokyo, Japan) in clinically relevant hypophosphatemic conditions.
Intact FGF23 (iFGF23) was measured in serum samples from 61 patients with FGF23-dependent hypophosphatemia (42-tumor induced osteomalacia [TIO] and 19-X-linked hypophosphatemia [XLH]); 8 patients with FGF23-independent hypophosphatemia (6-Fanconi Syndrome and 2-Vitamin D dependent rickets); 10 normophosphatemic patients; 15 chronic kidney disease (CKD) stage-2/3 and 20 CKD stage-4/5 patients; and a healthy control population. Disease-specific differences in measured iFGF23 concentrations and FGF23 concentration association with phosphate concentrations were reported.
iFGF23 concentrations were significantly elevated in 90% and 84% of TIO and XLH hypophosphatemia patients as compared to healthy controls (both TIO and XLH, P = .0001). There was no significant correlation between iFGF23 and phosphate concentrations (P = .74 and P = .86) for TIO and XLH, respectively. Patients with CKD showed a significant increase in serum iFGF23 as the estimated glomerular filtration rate decreased (ρ = -0.79, P ≤ 0.0001).
This study evaluated the clinical performance of the MedFrontier iFGF23 assay in a large cohort of XLH and TIO Caucasian and Asian patients. The clinical sensitivity of this iFGF23 assay is appropriate for clinical use.
Phosphatonins: From Discovery to Therapeutics
2023, Endocrine Practice
Phosphate is crucial for cell signaling, energy metabolism, nucleotide synthesis, and bone mineralization. The gut-bone-parathyroid-kidney axis is influenced by parathyroid hormone, 1,25-dihydroxyvitamin D, and phosphatonins, especially fibroblast growth factor 23 (FGF23). These hormones facilitate maintenance of phosphate homeostasis. This review summarizes current knowledge regarding the phosphate homeostasis, phosphatonin pathophysiology, and clinical implications of FGF23-related hypophosphatemic disorders, with specific focus on burosumab treatment.
A focused literature search of PubMed was conducted.
Phosphatonins including FGF23, secreted frizzled-related protein 4, matrix extracellular phosphoglycoprotein, and fibroblast growth factor 7 play a pathogenic role in several hypophosphatemic disorders. Excess FGF23 inhibits sodium-dependent phosphate cotransporters (NaPi-2a and NaPi-2c), resulting in hyperphosphaturia and hypophosphatemia. Additionally, FGF23 suppresses 1,25-dihydroxyvitamin D synthesis in the proximal renal tubule, and thus, it indirectly inhibits intestinal phosphate absorption. Disorders of FGF23-related hypophosphatemia include X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, fibrous dysplasia/McCune-Albright syndrome, and tumor-induced osteomalacia (TIO). Complications of conventional therapy with oral phosphate and vitamin D analogs comprise gastrointestinal distress, hypercalcemia, nephrocalcinosis, and secondary/tertiary hyperparathyroidism. In both children and adults with XLH and TIO, the anti-FGF23 antibody burosumab exhibits a favorable safety profile and is associated with healing of rickets in affected children and improvement of osteomalacia in both children and adults.
The treatment paradigm for XLH and TIO is changing based on data from recent clinical trials. Research suggest that burosumab is effective and safe for pediatric and adult patients with XLH or TIO.
Clinical practice recommendations for the diagnosis and treatment of X-linked hypophosphatemia: A consensus based on the ADAPTE method
2022, Medicina Clinica
El objetivo de este proyecto fue adaptar la primera guía de práctica clínica en la hipofosfatemia ligada al cromosoma X (XLH) aparecida en 2019 a nuestro medio siguiendo un proceso sistemático basado en el método ADAPTE.
La adaptación de las guías a nuestro ámbito de aplicación e implementación se llevó a cabo en 3 fases —puesta en marcha, adaptación y finalización— mediante un grupo de expertos implicados en el manejo de los pacientes con XLH.
Siguiendo la guía original, se presentan las recomendaciones acordadas por el grupo elaborador de las guías para el diagnóstico, la frecuencia y el ámbito de las visitas y el seguimiento específico en niños y adultos. Por otro lado, se establecen las recomendaciones para ambas franjas de edad con tratamiento convencional, así como con burosumab en niños o adultos y las relacionadas al controvertido uso de hormona de crecimiento en niños. También se proponen sugerencias en cuanto al seguimiento y al manejo de las alteraciones del aparato locomotor y tratamiento ortopédico en niños, la salud dental y la audición y las complicaciones neuroquirúrgicas. Por último, se plantean una serie de cuestiones y áreas en las que profundizar en una posible investigación futura.
Estas recomendaciones constituyen la adaptación sistemática a nuestro medio de la primera guía de práctica clínica basada en la evidencia para el diagnóstico y el manejo de la XLH, y esperamos que pueda contribuir al manejo adecuado de la enfermedad.
The objective of this project was to adapt to our setting following a systematic process based on the ADAPTE method the first clinical practice guidelines on X-linked hypophosphatemia (XLH) that were published in 2019.
The adaptation of the guidelines to our application and implementation setting was carried out in three phases —start-up, adaptation, and finalization— by a group of experts involved in the management of patients with XLH.
Following the original guide, the recommendations agreed by the group that elaborated the guidelines for diagnosis, frequency and scope of visits and specific follow-up in children and adults are presented. On the other hand, recommendations are established for both age groups with conventional treatment, as well as with burosumab in children or adults and those related to the controversial use of growth hormone in children. Suggestions are also proposed regarding the monitoring and management of musculoskeletal disorders and orthopedic treatment in children, dental health and hearing, and neurosurgical complications. Finally, a series of questions and areas are raised in order to deepen the possible future investigation.
These recommendations constitute the systematic adaptation to our setting of the first evidence-based clinical practice guide for the diagnosis and management of XLH and we hope that they can contribute to the adequate management of the disease.

View all citing articles on Scopus

View full text

Clinical usefulness of measurement of fibroblast growth factor 23 (FGF23) in hypophosphatemic patients: Proposal of diagnostic criteria using FGF23 measurement

Abstract

Introduction

Section snippets

Patients

Results

Discussion

Acknowledgments

Lancet

J Biol Chem

FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis

J Bone Miner Res

Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia

J Clin Endocrinol Metab

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

N Engl J Med

Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23

Nat Genet

Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism

Nat Genet

DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis

Nat Genet

Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia

Proc Natl Acad Sci U S A

FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting

J Clin Invest