Latent metabolic bone disease, skeletal dysplasia and other conditions related to low bone formation among 38 patients with subtrochanteric femoral fractures: a retrospective observational study.

Subtrochanteric femoral fracture is rare and intractable due to the possible association with low bone formation. Retrospective analysis of 38 patients with subtrochanteric femoral fractures revealed that four patients suffered from disorders related to low bone formation and there were specific treatments for two of them. PURPOSE: The main aim of this study was to detect latent metabolic bone diseases and skeletal dysplasia associated with low bone formation among patients with morphologic atypical femoral fracture (AFF). A second aim was to evaluate the frequency of recognized risk factors, such as antiresorptive agents, glucocorticoids, and age. METHODS: Clinical information was retrospectively analyzed among 38 Japanese patients who were admitted to the Department of Orthopedic Surgery and Spinal Surgery and the Division of Emergency and Critical Care Medicine at the University of Tokyo Hospital with diagnoses of subtrochanteric fractures between February 2012 and March 2022. RESULTS: Among 38 patients (including 30 females), 21 patients were aged 75 and over. Ten patients had past oral glucocorticoid use, and 18 had past antiresorptive agent use. Two patients were diagnosed with hypophosphatemic osteomalacia after the development of fractures. One patient was suspected to be a carrier of a loss-of-function variant of alkaline phosphatase, biomineralization associated (ALPL), and one other patient had previously been genetically diagnosed with pycnodysostosis. Among four patients with a diagnosis or suspicion of these metabolic bone diseases and skeletal dysplasia, four had past clinical fractures, two had past subtrochanteric femoral fractures, and two had subtrochanteric femoral fractures on both sides. CONCLUSION: If clinicians encounter patients with morphologic AFF, latent diseases related to low bone formation should be carefully differentiated because appropriate treatment may prevent delayed union and recurrent fractures. Additionally, it may be desirable to exclude these bone diseases in advance before initiating long-term use of antiresorptive agents in osteoporotic patients by screening with serum alkaline phosphatase levels to reduce the risk of morphologic AFF.

FGF-23, Left Ventricular Hypertrophy, and Mortality in Patients With CKD: A Revisit With Mediation Analysis.

Background: In patients with chronic kidney disease (CKD), fibroblast growth factor (FGF)-23 is suspected to cause death or cardiovascular disease by inducing left ventricular hypertrophy (LVH). Objectives: This study aims to quantify the mediational effect of LVH in the hypothetical causal pathway from FGF-23 to long-term adverse outcomes. Methods: From 3,939 adults with CKD stages 2 to 4 enrolled in the CRIC (Chronic Renal Insufficiency Cohort) study, 2,368 participants with available data of FGF-23, left ventricular mass index at 1 year, and covariates were included. We employed linear and Cox proportional hazards regression models to investigate the association between FGF-23 and LVH, all-cause mortality, atrial fibrillation (AF), or congestive heart failure (CHF). Mediation analysis was used within a counterfactual framework to decompose the effect of FGF-23 into natural direct and indirect effects. Results: Among 2,368 participants (mean age: 57.7 years, 1,252 males, median FGF-23 level: 138.8 RU/mL), left ventricular mass index was positively correlated with FGF-23. During a median of 12.0, 11.1, and 11.1 years, FGF-23 was associated with all-cause mortality (HR: 1.62, 95% CI: 1.24-2.12), AF (HR: 1.58, 95% CI: 1.12-2.24), and CHF (HR: 1.32, 95% CI: 0.95-1.84) when the highest quartile was compared to the lowest quartile. LVH mediated 7.4%, 11.2%, and 21.9% of the effect of FGF-23 on all-cause mortality, AF, and CHF, respectively. Conclusions: In CKD patients, FGF-23 had a minor effect on the development of long-term adverse outcomes through LVH. Other potential mediators and the validity of negative effect of FGF-23 should be explored.

Cardiovascular Outcomes of KCNJ5 Mutated Aldosterone-Producing Adenoma: A Systematic Review.

BACKGROUND: While clinical features of KCNJ5-mutated aldosterone-producing adenoma (APA) have been reported, evidence of its clinical outcomes is lacking. We aimed to synthesize available literature about the associations between KCNJ5 mutation with cardiovascular and metabolic outcomes among patients with APA. METHODS: In this systematic review of observational studies, MEDLINE and Embase were searched through August 2022. Two independent authors screened the search results and extracted data from eligible observational studies investigating cardiovascular or metabolic outcomes between KCNJ5-mutated APAs and KCNJ5-non-mutated APAs. Risk of Bias In Non-randomized Studies of Interventions was used to assess the quality of the included studies. RESULTS: A total of 573 titles/abstracts were screened and after the expert opinion of the literature, full text was read in 20 titles/abstracts, of which 12 studies were included. Across 3 studies comparing the baseline or change in the cardiac function between KCNJ5-mutated APAs and KCNJ5-non-mutated APAs, all studies reported the association between impaired cardiac functions and KCNJ5 mutation status. Among 6 studies evaluating the cure of hypertension after surgery, all studies showed that KCNJ5 mutation was significantly associated with the cure of hypertension. In quality assessment, 7 studies were at serious risk of bias, while the remaining studies were at moderate risk of bias. CONCLUSIONS: This systematic review provided evidence of the significant association between KCNJ5 mutation and unfavorable cardiovascular outcomes in patients with primary aldosteronism. Further research is needed to improve the quality of evidence on this topic and elucidate the underlying mechanisms of the potential burden of KCNJ5 mutation.

Acquired Forms of Fibroblast Growth Factor 23-Related Hypophosphatemic Osteomalacia.

Fibroblast growth factor 23 (FGF23) is a pivotal humoral factor for the regulation of serum phosphate levels and was first identified in patients with autosomal dominant hypophosphatemic rickets and tumor-induced osteomalacia (TIO), the most common form of acquired FGF23-related hypophosphatemic rickets/osteomalacia (FGF23rHR). After the identification of FGF23, many other inherited and acquired forms of FGF23rHR were reported. In this review article, the detailed features of each acquired FGF23rHR are discussed, including TIO, ectopic FGF23 syndrome with malignancy, fibrous dysplasia/McCune-Albright syndrome, Schimmelpenning-Feuerstein-Mims syndrome/cutaneous skeletal hypophosphatemia syndrome, intravenous iron preparation-induced FGF23rHR, alcohol consumption-induced FGF23rHR, and post-kidney transplantation hypophosphatemia. Then, an approach for the differential diagnosis and therapeutic options for each disorder are concisely introduced. Currently, the majority of endocrinologists might only consider TIO when encountering patients with acquired FGF23rHR; an adequate differential diagnosis can reduce medical costs and invasive procedures such as positron emission tomography/computed tomography and venous sampling to identify FGF23-producing tumors. Furthermore, some acquired FGF23rHRs, such as intravenous iron preparation/alcohol consumption-induced FGF23rHR, require only cessation of drugs or alcohol to achieve full recovery from osteomalacia.

The pathophysiology of hypophosphatemia.

After identification of fibroblast growth factor (FGF) 23 as the pivotal regulator of chronic serum inorganic phosphate (Pi) levels, the etiology of disorders causing hypophosphatemic rickets/osteomalacia has been clarified, and measurement of intact FGF23 serves as a potent tool for differential diagnosis of chronic hypophosphatemia. Additionally, measurement of bone-specific alkaline phosphatase (BAP) is recommended to differentiate acute and subacute hypophosphatemia from chronic hypophosphatemia. This article divides the etiology of chronic hypophosphatemia into 4 groups: A. FGF23 related, B. primary tubular dysfunction, C. disturbance of vitamin D metabolism, and D. parathyroid hormone 1 receptor (PTH1R) mediated. Each group is further divided into its inherited form and acquired form. Topics for each group are described, including "ectopic FGF23 syndrome," "alcohol consumption-induced FGF23-related hypophosphatemia," "anti-mitochondrial antibody associated hypophosphatemia," and "vitamin D-dependent rickets type 3." Finally, a flowchart for differential diagnosis of chronic hypophosphatemia is introduced.

The Effect of Asfotase Alfa on Plasma and Urine Pyrophosphate Levels and Pseudofractures in a Patient With Adult-Onset Hypophosphatasia.

Hypophosphatasia (HPP) is an inherited disease caused by variants of the ALPL gene encoding tissue-nonspecific alkaline phosphatase. Adult-onset HPP (adult HPP), known as a mild form of HPP, develops symptoms involving osteomalacia after the age of 18 years. Asfotase alfa (AA) is a modulated recombinant human alkaline phosphatase (ALP) that has been established as a first-line therapy for severe forms of HPP, such as perinatal and infantile forms. We described a 64-year-old female who presented with pseudofractures in bilateral femur diaphyses and impaired mobility. Low serum ALP activity and a high concentration of urine phosphoethanolamine indicated the diagnosis of HPP, which was confirmed by the identification of a homozygous variant in the ALPL gene (c.319G > A; p.Val107Ile). An in vitro transfection experiment to measure the ALP activity of this novel variant protein was performed, resulting in 40% of the residual enzymatic activity compared with the wild type. AA was initiated to facilitate the union of pseudofracture and to improve mobility. After 6 months, radiographic images revealed the disappearance of fracture lines, and improvement of ambulatory ability was confirmed by the 6-minute walk test (525 to 606 m). The EQ-5D-5L index was also improved (0.757 to 0.895). Within a follow-up period, the levels of urine pyrophosphate corrected by urine creatinine (uPPi/Cre) declined in parallel with the level of plasma PPi (plasma PPi: 6.34 to 1.04 µM, uPPi/Cre: 226.8 to 75.4 nmol/mg). The beneficial effect of AA on pseudofracture healing in adult HPP was presented, although the application of AA should be restricted to patients exhibiting relatively severe manifestations. In addition, a novel pathogenic variant of the ALPL gene was identified with the supportive result of functional analysis. Furthermore, when monitoring patients with HPP treated with AA, uPPi/Cre might be a convenient substitute for plasma PPi, which requires immediate filtration after blood sampling. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

FGF23-related hypophosphatemia in a patient with small cell lung cancer: a case report and literature review.

Although there are a few case reports of patients with small cell lung cancer developing hypophosphatemia, detailed information on this condition is scarce. A 52-year-old patient with advanced stage small cell lung cancer developed hypophosphatemia (1.1 mg/dL) during chemotherapy. A reduced level of the tubular reabsorption of phosphate concomitant with an inappropriately elevated level of fibroblast growth factor (FGF) 23 (48.4 pg/mL) was noted, leading to the diagnosis of FGF23-related hypophosphatemia. Laboratory data also showed hypercortisolemia with an elevated ACTH level and hyponatremia with an inappropriately unsuppressed level of antidiuretic hormone (ADH). These data suggested the overproduction of FGF23 in addition to ACTH and ADH. Because the octreotide loading test did not present a suppressive effect on ACTH or FGF23 levels, the patient was treated with phosphate supplementation, active vitamin D and metyrapone, which partially improved the serum phosphate and cortisol levels. Even after two subsequent courses of chemotherapy, the small cell lung cancer progressed, and the FGF23 level was further elevated (83.7 pg/mL). Although it is very rare, FGF23-related hypophosphatemia is one of the hormonal disturbances that could be observed in patients with small cell lung cancer. This article reviews similar clinical conditions and revealed that advanced states of malignancy seemed to be associated with the development of renal wasting hypophosphatemia, especially in lung cancer and prostate cancer. Therefore, the parameters related to hypophosphatemia should be monitored in patients with advanced small cell lung cancer to prevent the development of hypophosphatemic osteomalacia.

Clinical performance of a new intact FGF23 immunoassay in healthy individuals and patients with chronic hypophosphatemia.

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.

Effect of Conventional Treatment on Dental Complications and Ectopic Ossifications Among 30 Adults With XLH.

CONTEXT: Conventional treatment of X-linked hypophosphatemia (XLH) was reported to prevent dental complications, but whether the preventive effect was different among different types of teeth, including anterior teeth and molar teeth, is uncertain. Evidence of the preventive effect of conventional treatment on ectopic ossifications is also limited. OBJECTIVE: To compare dental complications and ectopic ossifications among adults with XLH with early (<5 years old) or late (≥5 years old) conventional treatment. METHODS: This retrospective observational study included a total of 30 adults with XLH; orthopantomograms, spinal computed tomography scans, and X-rays of hip/knee joints were studied. Dental complications, including the decayed, missing, filled (DMF) index and devitalized teeth, apical periodontitis, and periodontitis, were evaluated. The ossification of the anterior/posterior longitudinal ligament and yellow ligament indexes (OA/OP/OY indexes) and the sum of the OA/OP/OY indexes (OS index) were utilized to evaluate the severity of spinal ligament ossification. The severity of the hip/knee osteophytes was evaluated using the Kellgren-Lawrence (KL) classification. RESULTS: The number of sound teeth was significantly lower and the DMF index was significantly higher in patients with late treatment. The severity of dental complications in the anterior tooth and molar tooth, OA/OP/OY/OS index, and KL grade were not significantly different among patients with early treatment and those with late treatment. CONCLUSION: Early treatment could prevent dental complications but did not prevent ectopic ossification in adult patients with XLH. The difference in the preventive effect was not observed among different types of teeth.

Utility of Multimodality Approach Including Systemic FGF23 Venous Sampling in Localizing Phosphaturic Mesenchymal Tumors.

Context: Tumor-induced osteomalacia (TIO) is one of the most common forms of acquired fibroblast growth factor 23 (FGF23)-related hypophosphatemia and is usually caused by phosphaturic mesenchymal tumors (PMTs). Although the complete resection of PMTs can cure TIO, preoperative localization of tumors by standard imaging modalities is often challenging. In addition to 18F-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography (FDG-PET) and 111In-pentetreotide scintigraphy (SRS), systemic FGF23 venous sampling (FGF23VS) has been used to help localize PMTs in specialized institutions. Objective: This study aimed to evaluate the diagnostic performance of each imaging test and their combinations in localizing PMTs. Methods: In an observational retrospective study of patients with adult-onset FGF23-related osteomalacia who underwent all 3 imaging studies (FDG-PET, SRS, and FGF23VS), the rate of successful preoperative localization of the tumors was evaluated only in the patients with pathological diagnoses of PMTs, considering the possibility that pathogenesis of patients without identified tumors might be due to other causes such as late-onset hereditary FGF23-related hypophosphatemia. Results: A total of 30 Japanese patients with TIO (median age, 60 years [range, 28-87 years]; 10 women [33.3%]) were included in the study. The success rate of preoperative localization for each test and combinations of 2 or 3 tests among 18 patients with PMTs was as follows: 72% (FDG-PET), 72% (SRS), 94% (FGF23VS), 89% (FDG-PET, SRS), 100% (FDG-PET, FGF23VS), 94% (SRS, FGF23VS), and 100% (FDG-PET, SRS, and FGF23VS). Conclusion: We observed the highest localization rate of PMTs in patients with identified PMTs with the combination of FDG-PET and FGF23VS.

Incidence of ossification of the spinal ligaments in acromegaly patients.

Some previous case reports have implied a relationship between acromegaly and ossification of the spinal ligaments. However, there have been no reports of a case series exploring the incidence of ossification of the spinal ligaments in patients with acromegaly. To this end, computed tomography (CT) of the spine in 10 consecutive patients with acromegaly was examined in this study. Five out of 10 patients had ossification of the spinal ligaments. Among them, two patients had ossification of the posterior longitudinal ligament (OPLL), which was noticeably higher than the prevalence of OPLL in the general adult population (1.9-4.3 %). Body mass index was significantly higher in the group with spinal ligament ossification (p = 0.03), but there were no significant differences in age, sex, serum phosphate, albumin-adjusted calcium, growth hormone (GH), standard deviation of insulin-like growth factor-1 (IGF-1), or the incidence of diabetes mellitus between the groups with or without ossification of the spinal ligaments. The ossification index (OS index) was used to determine the severity of spinal ligament ossification, and there were no significant correlations between the OS index and GH or IGF-1 (p = 0.51 and 0.75, respectively). This study was the first to report a high prevalence of spinal ossification in patients with acromegaly. In conclusion, this study suggested a possible association between acromegaly and ossification of the spinal ligaments, although the number of patients was insufficient to draw a conclusion. Acromegaly patients should be tested to confirm, or rule out, spinal ossification, and further studies to clarify the underlying mechanism of spinal ossification in acromegaly patients are warranted.

Machine Learning-Based Prediction of Elevated PTH Levels Among the US General Population.

CONTEXT: Although elevated parathyroid hormone (PTH) levels are associated with higher mortality risks, the evidence is limited as to when PTH is expected to be elevated and thus should be measured among the general population. OBJECTIVE: This work aimed to build a machine learning-based prediction model of elevated PTH levels based on demographic, lifestyle, and biochemical data among US adults. METHODS: This population-based study included adults aged 20 years or older with a measurement of serum intact PTH from the National Health and Nutrition Examination Survey (NHANES) 2003 to 2006. We used the NHANES 2003 to 2004 cohort (n = 4096) to train 6 machine-learning prediction models (logistic regression with and without splines, lasso regression, random forest, gradient-boosting machines [GBMs], and SuperLearner). Then, we used the NHANES 2005 to 2006 cohort (n = 4112) to evaluate the model performance including area under the receiver operating characteristic curve (AUC). RESULTS: Of 8208 US adults, 753 (9.2%) showed PTH greater than 74 pg/mL. Across 6 algorithms, the highest AUC was observed among random forest (AUC [95% CI] = 0.79 [0.76-0.81]), GBM (AUC [95% CI] = 0.78 [0.75-0.81]), and SuperLearner (AUC [95% CI] = 0.79 [0.76-0.81]). The AUC improved from 0.69 to 0.77 when we added cubic splines for the estimated glomerular filtration rate (eGFR) in the logistic regression models. Logistic regression models with splines showed the best calibration performance (calibration slope [95% CI] = 0.96 [0.86-1.06]), while other algorithms were less calibrated. Among all covariates included, eGFR was the most important predictor of the random forest model and GBM. CONCLUSION: In this nationally representative data in the United States, we developed a prediction model that potentially helps us to make accurate and early detection of elevated PTH in general clinical practice. Future studies are warranted to assess whether this prediction tool for elevated PTH would improve adverse health outcomes.

Clinical Challenges in Diagnosis, Tumor Localization and Treatment of Tumor-Induced Osteomalacia: Outcome of a Retrospective Surveillance.

Tumor-induced osteomalacia (TIO) is an acquired fibroblast growth factor 23 (FGF23)-related hypophosphatemic osteomalacia caused by phosphaturic mesenchymal tumors (PMTs) developed in the bone or soft tissue. Diagnostic delay should be addressed, and ideal techniques to localize PMTs and efficient treatment options should be explored to improve the outcomes of this rare disease. To clarify the detailed clinical course and outcomes of TIO patients, retrospective questionnaire surveys were conducted among physicians from the Japanese Society for Bone and Mineral Research (JSBMR) and the Japan Endocrine Society (JES). The primary survey collected the number of TIO patients between January 2007 and December 2018. The secondary survey aimed to obtain the detailed characteristics, laboratory data, and outcomes. Eighty-eight patients (52 males, mean: 52 years old) were included, and 24 patients were clinically diagnosed with TIO without localized PMTs. The median duration from the onset to detection of high FGF23 levels was 3.4 years, with 77 patients being initially misdiagnosed. Among the methods used to detect small, localized PMTs (≤10 mm), fluorine-18-fluorodeoxyglucose-positron emission tomography/computed tomography and somatostatin receptor scintigraphy were less sensitive than somatostatin receptor positron emission tomography/computed tomography (SRPET/CT). Systemic venous sampling (SVS) of FGF23 was performed in 53 patients; among them, SVS was considered useful for detecting localized PMTs in 45 patients with diverse tumor sizes. Finally, 45 patients achieved biochemical remission by surgery, 39 patients continued pharmaceutical treatment, including burosumab (11 patients), and four patients died. These results encouraged us to further increase the awareness of TIO and to improve the accessibility of SRPET/CT and SVS. Further evidence about the efficacy of new pharmaceutical treatments is awaited. © 2022 American Society for Bone and Mineral Research (ASBMR).

Identification of ENPP1 Haploinsufficiency in Patients With Diffuse Idiopathic Skeletal Hyperostosis and Early-Onset Osteoporosis.

Homozygous ENPP1 mutations are associated with autosomal recessive hypophosphatemic rickets type 2 (ARHR2), severe ossification of the spinal ligaments, and generalized arterial calcification of infancy type 1. There are a limited number of reports on phenotypes associated with heterozygous ENPP1 mutations. Here, we report a series of three probands and their families with heterozygous and compound heterozygous ENPP1 mutations. The first case (case 1) was a 47-year-old male, diagnosed with early-onset osteoporosis and low-normal serum phosphate levels, which invoked suspicion for hypophosphatemic rickets. The second and third cases were 77- and 54-year-old females who both presented with severe spinal ligament ossification and the presumptive diagnosis of diffuse idiopathic skeletal hyperostosis (DISH). Upon workup, fibroblast growth factor 23 (FGF23) was noted to be relatively high in case 2 and serum phosphorous was low-normal in case 3, and the diagnoses of X-linked hypophosphatemic rickets (XLH) and ARHR2 were considered. Genetic testing for genes related to congenital hypophosphatemic rickets was therefore performed, revealing heterozygous ENPP1 variants in cases 1 and 2 (case 1, c.536A>G, p.Asn179Ser; case 2, c.1352A>G, p.Tyr451Cys) and compound heterozygous ENPP1 variants in case 3 constituting the same variants present in cases 1 and 2 (c.536A>G, p.Asn179Ser and c.1352A>G, p.Tyr451Cys). Several in silico tools predicted the two variants to be pathogeneic, a finding confirmed by in vitro biochemical analysis demonstrating that the p.Asn179Ser and p.Tyr451Cys ENPP1 variants possessed a catalytic velocity of 45% and 30% compared with that of wild-type ENPP1, respectively. Both variants were therefore categorized as pathogenic loss-of-function mutations. Our findings suggest that ENPP1 mutational status should be evaluated in patients presenting with the diagnosis of idiopathic DISH, ossification of the posterior longitudinal ligament (OPLL), and early-onset osteoporosis. © 2022 American Society for Bone and Mineral Research (ASBMR).

Radiological evaluation of pseudofracture after the administration of asfotase alfa in an adult with benign prenatal hypophosphatasia: A case report.

Hypophosphatasia (HPP) is a congenital disorder with decreased activity of tissue-nonspecific alkaline phosphatase. Asfotase alfa is the only treatment approved for HPP and improves the impairment of bone mineralization. Although several previous studies have reported the efficacy of asfotase alfa to treat fractures and pseudofractures in patients with HPP, there are only a few reports with a detailed description of the healing process. In this case report, we present an 18-year-old female patient with benign prenatal HPP who received asfotase alfa to treat her pseudofracture. At the age of 17, a pseudofracture developed in her left tibia after repetitive gymnastic exercise for months. Following observation over a year, she was referred to our department. X-ray images indicated a narrow radiolucent band in the mid-diaphysis of her left tibia, and bone scintigraphy showed nuclide accumulation in the same region. Replacement therapy with asfotase alfa was started, resulting in pain relief in two months, and the disappearance of nuclide accumulation on bone scintigraphy and union of the pseudofracture on X-ray after two years. This is the first case report describing the detailed pseudofracture healing process in a patient with benign prenatal HPP initiating asfotase alfa.

Performance evaluation of the new chemiluminescent intact FGF23 assay relative to the existing assay system.

INTRODUCTION: This study assessed the performance of a new fully automated immunoassay for fibroblast growth factor (FGF) 23 (Determinar CL FGF23 CL) among healthy individuals and those with chronic hypophosphatemia compared with the previous assay (Kainos FGF23 KI). MATERIALS AND METHODS: A total of 380 serum samples from healthy participants were collected to determine the reference range of FGF23 levels with CL. A total of 200 serum samples from 22 hypophosphatemic patients were collected simultaneously to compare the difference in FGF23 levels between CL and KI. The Mann-Whitney U test and linear regression analysis were adopted to assess the differences and linearity between the two assays. RESULTS: The median FGF23 levels among healthy individuals was 31.7 (interquartile: 26.4-37.5) pg/mL. When the reference range was calculated as the mean ± 2 standard deviation (2SD), it was 16.1-49.3 pg/mL. A total of 363 individuals (96%) among normal cases fell in this range. Among 200 samples from patients with chronic hypophosphatemic disorder, the median FGF23 levels analyzed by CL and KI were 123.0 (90.2-237.7) and 172.5 (115.8-290.7) pg/mL. KI yielded significantly higher FGF23 values than CL (p < 0.001). A linear regression model revealed the correlation between KI (x) and CL (y), which had a slope of 0.76 with a y-intercept of -0.32 and high linearity (R2 = 0.99). CONCLUSION: The new measurement kit yielded lower FGF23 values when compared with the previous assay. Clinicians should consider this discrepancy when they assay intact FGF23 values with CL.

Induction of FGF23-related hypophosphatemic osteomalacia by alcohol consumption.

CONTEXT: Fibroblast growth factor (FGF) 23 is a hormone that regulates serum phosphate levels, the excess action of which causes chronic hypophosphatemic rickets/osteomalacia. To date, there are only two identified causes of acquired FGF23-related hypophosphatemic osteomalacia: tumor-induced osteomalacia (TIO) and osteomalacia induced by the intravenous infusion of some forms of iron preparations. In the current study, two cases of FGF23-related hypophosphatemia probably induced by chronic alcohol consumption were first introduced. CASE DESCRIPTION: Case 1 and case 2 had been drinking high amounts of alcohol for more than twenty years until they were admitted to the hospital. Case 1 was a 43-year-old man with progressive worsening multiple pains and muscle weakness who exhibited chronic hypophosphatemia with increased intact FGF23 levels. A week after admission, the serum phosphate level recovered to the reference range, and the intact FGF23 level declined. Case 1 resumed drinking after discharge, and hypophosphatemia concomitant with high intact FGF23 levels recurred. The alleviation of FGF23-related hypophosphatemia was observed each time he temporarily abstained from drinking for a short period. Case 2 was a 60-year-old man with recurrent fractures and exacerbation of pain in multiple joints who also exhibited hypophosphatemia with increased intact FGF23 levels. After admission, the serum phosphate level gradually increased to the lower limit of the normal range. The intact FGF23 level decreased, but it was still higher than 30 pg/ml, and causative FGF23-producing tumors were not identified even with thorough examinations, including somatostatin receptor scintigraphy, fluorine-18-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT) and systemic venous FGF23 sampling. He completely abstained from alcohol after discharge. Along with the serum phosphate level, intact FGF23 was subsequently decreased and had been normalized for 5 months. Both patients had no genetic mutation related to hereditary FGF23-related hypophosphatemic rickets/osteomalacia, including autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR). CONCLUSION: Two cases of FGF23-related hypophosphatemia probably induced by alcohol were first introduced in this study. Identifying this reversible condition among acquired FGF23-related hypophosphatemic osteomalacia is critical to obtain better patient outcomes and save medical resources. This condition is similar to iron infusion-induced FGF23-related hypophosphatemia in terms of the dysregulation of FGF23 due to exogenous factors. Future research to elucidate the precise mechanism of these conditions is warranted.

Altered Thyroid Function Tests Observed in Hypophosphatasia Patients Treated with Asfotase Alfa.

BACKGROUND: Asfotase alfa is the only approved treatment that can normalize mineralization in patients with hypophosphatasia (HPP). Its interference in alkaline phosphatase (ALP) dependent immunoassays has been reported. OBJECTIVE: To describe thyroid function tests interfered with by asfotase alfa and elucidate the underlying mechanism. Patients and Methods. Three patients with HPP treated with asfotase alfa were included. Thyroid hormone levels measured using five different immunoassays with or without ALP as a labeling enzyme during asfotase alfa treatment were evaluated. RESULTS: After the initiation of asfotase alfa, three HPP patients showed low free triiodothyronine (FT3) and free thyroxine (FT4) measured with AIA-2000 (Tosoh, Tokyo, Japan), an enzyme immunoassay system that uses ALP as a labeling enzyme, but their thyroid-stimulating hormone (TSH) levels were within the normal range. The other CLEIA system using ALP as a label, AIA-CL2400 (Tosoh, Tokyo, Japan), and ALP-independent immunoassay systems demonstrated normal FT3 and FT4 levels. These data suggested that although the thyroid function of these three patients was normal, asfotase alfa interfered with the thyroid hormone measurements made with AIA-2000. AIA-2000 and AIA-CL2400 adopted one-step and delayed one-step measurements, respectively, and the same antibody was used for both immunoassays. However, asfotase alfa may be absorbed on the magnetic beads used in the AIA reagent with the AIA-2000 system but not absorbed on the microparticles used in AIA-CL2400. CONCLUSION: Clinicians should be aware of the possible interference in thyroid function measurements by adopting specific types of immunoassays in asfotase alfa-treated HPP patients.