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.

Osteoporotic fracture risk in women with breast cancer treated with aromatase inhibitors: a health insurance claims database study in Japan.

BACKGROUND: Hormone therapy with aromatase inhibitors (AIs) for estrogen receptor-dependent breast cancer may expose patients to an increased osteoporosis risk. This study was performed to estimate fracture risk in women with breast cancer to whom AIs were prescribed in Japan. METHODS: This retrospective study used data from the Japanese Medical Data Vision database. Women with breast cancer prescribed AIs over a 12-month period were identified and matched to women not prescribed AIs using a propensity score. Fracture rates were estimated by a cumulative incidence function and compared using a cause-specific Cox hazard model. The proportion of women undergoing bone density tests was retrieved. RESULTS: For all fractures sites combined, cumulative fracture incidence at 10 years was 0.19 [95%CI: 0.16-0.22] in women prescribed AIs and 0.18 [95%CI: 0.15-0.21] without AIs. AI prescription was not associated with any changes in risk (adjusted hazard ratio: 1.08 [95%CI: 0.99-1.17] p = 0.08). Women prescribed AI more frequently underwent bone density testing (31.9% [95% CI: 31.2%; 32.6%] versus 2.2% [95% CI: 2.0%; 2.4%]). CONCLUSIONS: The anticipated association between AI exposure and osteoporotic fracture risk in Japanese women with breast cancer was not seen clearly.

Recent advances in fibroblast growth factor 23-related hypophosphatemic disorders.

PURPOSE OF REVIEW: Fibroblast growth factor 23 (FGF23) is a hormone to reduce blood phosphate concentration. Excessive actions of FGF23 induce FGF23-related hypophosphatemic disorders, such as X-linked hypophosphatemic rickets (XLH) and tumor-induced osteomalacia (TIO). We will summarize recent advances in the diagnosis and treatment of FGF23-related hypophosphatemic disorders. RECENT FINDINGS: The measurement of blood FGF23 is useful to make a diagnosis of FGF23-related hypophosphatemic disorders. It was reported that many patients with FGF23-related hypophosphatemic disorders, especially TIO, were misdiagnosed, therefore, it is necessary to enhance the awareness of these diseases. A novel method to inhibit excessive actions of FGF23 by a human monoclonal antibody for FGF23, burosumab, has been approved in several countries. In more long-term observation than clinical trials, burosumab has also been shown to improve biochemical abnormalities and symptoms of rickets/osteomalacia. Following these advances, several registries and consensus recommendations on FGF23-related hypophosphatemic disorders, especially XLH, have been established in each country or region. SUMMARY: Further long-term effects of burosumab and the precise mechanism of FGF23 overproduction in patients with FGF23-related hypophosphatemic disorders need to be clarified in the future studies.

Androgen deprivation therapy-related fracture risk in prostate cancer: an insurance claims database study in Japan.

INTRODUCTION: Androgen deprivation therapy (ADT) is widely used for the treatment of prostate cancer. ADT is associated with reduced bone density leading to an increased risk of osteoporotic fracture. The objective of this retrospective cohort study was to quantify fracture risk in men treated with ADT for prostate cancer in real-world practice in Japan. MATERIALS AND METHODS: Data were extracted from the Japanese Medical Data Vision (MDV) database. Men initiating ADT for treatment of prostate cancer between April 2010 and March 2021 were identified and matched to a cohort of prostate cancer patients not taking ADT using a propensity score. Fracture rates were estimated by a cumulative incidence function and compared between cohorts using a Cox cause-specific hazard model. Information was extracted on demographics, comorbidities and bone densitometry. RESULTS: 30,561 men with PC starting ADT were matched to 30,561 men with prostate cancer not treated with ADT. Following ADT initiation, <5% of men underwent bone densitometry. Prescription of ADT was associated with an increased fracture risk compared to not taking ADT (adjusted hazard ratio: 1.63 [95% CI 1.52-1.75]). CONCLUSION: ADT is associated with a 1.6-fold increase in the risk of osteoporotic fracture in men with prostate cancer. Densitometry in this population is infrequent and monitoring urgently needs to be improved in order to implement effective fracture prevention.

The 2023 Guidelines for the management and treatment of glucocorticoid-induced osteoporosis.

INTRODUCTION: Although synthetic glucocorticoids (GCs) are commonly used to treat autoimmune and other diseases, GC induced osteoporosis (GIOP) which accounts for 25% of the adverse reactions, causes fractures in 30-50% of patients, and markedly decreases their quality of life. In 2014, the Japanese Society for Bone and Mineral Research (JSBMR) published the revised guidelines for the management and treatment of steroid-induced osteoporosis, providing the treatment criteria based on scores of risk factors, including previous fractures, age, GC doses, and bone mineral density, for patients aged ≥18 years who are receiving GC therapy or scheduled to receive GC therapy for ≥3 months. MATERIALS AND METHODS: The Committee on the revision of the guidelines for the management and treatment of GIOP of the JSBMR prepared 17 clinical questions (CQs) according to the GRADE approach and revised the guidelines for the management and treatment of GIOP through systematic reviews and consensus conferences using the Delphi method. RESULTS: Bisphosphonates (oral and injectable formulations), anti-RANKL antibody teriparatide, eldecalcitol, or selective estrogen receptor modulators are recommended for patients who has received or scheduled for GC therapy with risk factor scores of ≥3. It is recommended that osteoporosis medication is started concomitantly with the GC therapy for the prevention of fragility fractures in elderly patients. CONCLUSION: The 2023 guidelines for the management and treatment of GIOP was developed through systematic reviews and consensus conferences using the Delphi method.

Familial cases with adult-onset FGF23-related hypophosphatemic osteomalacia -A PHEX 3'-UTR change as a possible cause.

Excessive actions of FGF23 cause several kinds of hypophosphatemic rickets/osteomalacia. It is possible that there still remain unknown causes or mechanisms for FGF23-related hypophosphatemic diseases. We report two male cousins who had been suffering form FGF23-related hypophosphatemic osteomalacia. Sequencing of exons and exon-intron junctions of known causative genes for FGF23-related hypophosphatemic diseases and whole genome sequencing were conducted. Luciferase assay was used to evaluate the effect of a detected nucleotide change on mRNA stability. Two cousins showed hypophosphatemia with impaired proximal tubular phosphate reabsorption and high FGF23. Serum phosphate of their mothers was within the reference range. Exome sequencing of the proband detected no mutations. Whole genome sequencing of the patients and their mothers identified a nucleotide change in the 3'-UTR of phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) gene (c.*1280_*1287dupGTGTGTGT) which is heterozygous in the mothers and hemizygous in the patients. While sixteen is the most prevalent number of GT repeats, this family had twenty repeats. Luciferase assay indicated that mRNA with 3'-UTR of PHEX with 20 GT repeats was more unstable than that with 16 repeats. Sequencing of exons and exon-intron junctions of known causative genes for FGF23-related hypophosphatemic diseases cannot identify all the genetic causes. Our results strongly suggest that changes of PHEX expression by a nucleotide change in the 3'-UTR is a novel mechanism of FGF23-related hypophosphatemic osteomalacia.

Regulation of FGF23 Production in Osteocytes.

PURPOSE OF REVIEW: FGF23 is a bone-derived hormone working to reduce serum phosphate level. This review focuses on recent findings regarding regulatory mechanisms of FGF23 expression in osteocytes, FGF23 levels, and activities. RECENT FINDINGS: Circulatory FGF23 levels reflecting FGF23 biological activities can be regulated by both FGF23 expression and posttranslational modification of FGF23 protein. O-linked glycosylation and phosphorylation of FGF23 protein as well as enzymes that can cleave FGF23 protein are involved in the posttranslational modification. However, precise mechanisms of FGF23 protein processing are not clear. Several extracellular factors have been shown to affect FGF23 levels in kidney injuries. Contribution of these factors may be different depending on the causes and stages of kidney injury. FGF23 activities are regulated by complex mechanisms involving transcriptional and posttranslational modulations. There still remain several questions regarding the regulatory mechanisms of FGF23 expression and FGF23 processing.

In vivo treatment with calcilytic of CaSR knock-in mice ameliorates renal phenotype reversing downregulation of the vasopressin-AQP2 pathway.

High concentrations of urinary calcium counteract vasopressin action via the activation of the Calcium-Sensing Receptor (CaSR) expressed in the luminal membrane of the collecting duct cells, which impairs the trafficking of aquaporin-2 (AQP2). In line with these findings, we provide evidence that, with respect to wild-type mice, CaSR knock-in (KI) mice mimicking autosomal dominant hypocalcaemia, display a significant decrease in the total content of AQP2 associated with significantly higher levels of AQP2 phosphorylation at Ser261, a phosphorylation site involved in AQP2 degradation. Interestingly, KI mice also had significantly higher levels of phosphorylated p38MAPK, a downstream effector of CaSR and known to phosphorylate AQP2 at Ser261. Moreover, ATF1 phosphorylated at Ser63, a transcription factor downstream of p38MAPK, was significantly higher in KI. In addition, KI mice had significantly higher levels of AQP2-targeting miRNA137 consistent with a post-transcriptional downregulation of AQP2. In vivo treatment of KI mice with the calcilytic JTT-305, a CaSR antagonist, increased AQP2 expression and reduced AQP2-targeting miRNA137 levels in KI mice. Together, these results provide direct evidence for a critical role of CaSR in impairing both short-term vasopressin response by increasing AQP2-pS261, as well as AQP2 abundance, via the p38MAPK-ATF1-miR137 pathway. KEY POINTS: Calcium-Sensing Receptor (CaSR) activating mutations are the main cause of autosomal dominant hypocalcaemia (ADH) characterized by inappropriate renal calcium excretion leading to hypocalcaemia and hypercalciuria. Current treatments of ADH patients with parathyroid hormone, although improving hypocalcaemia, do not improve hypercalciuria or nephrocalcinosis. In vivo treatment with calcilytic JTT-305/MK-5442 ameliorates most of the ADH phenotypes of the CaSR knock-in mice including hypercalciuria or nephrocalcinosis and reverses the downregulation of the vasopressin-sensitive aquaporin-2 (AQP2) expression, providing direct evidence for a critical role of CaSR in impairing vasopressin response. The beneficial effect of calcilytic in reducing the risk of renal calcification may occur in a parathyroid hormone-independent action through vasopressin-dependent inhibition of cAMP synthesis in the thick ascending limb and in the collecting duct. The amelioration of most of the abnormalities in calcium metabolism including hypercalciuria, renal calcification, and AQP2-mediated osmotic water reabsorption makes calcilytic a good candidate as a novel therapeutic agent for ADH.

Tumor-induced osteomalacia.

Tumor-induced osteomalacia is one of paraneoplastic syndromes characterized by hypophosphatemia caused by excessive actions of fibroblast growth factor 23 (FGF23). Since the cloning of FGF23 about 20 years ago, more widespread awareness of this disease has been achieved. However, there still remain several difficulties in the management of patients with this disease. In this review, these clinical problems are discussed together with the physiological and pathophysiological functions of FGF23. Personal proposals in the management of patients with suspected patients with tumor-induced osteomalacia are also presented.

VDR is an essential regulator of hair follicle regression through the progression of cell death.

Vitamin D receptor (VDR) is essential for hair follicle homeostasis as its deficiency induces hair loss, although the mechanism involved remains unknown. Our research shows that, in Vdr-knockout mice, the hair cycle is halted during the catagen stage, preceding alopecia. In addition, in Vdr-knockout hair follicles, epithelial strands that normally regress during the catagen phase persist as "surviving epithelial strands." Single-cell RNA sequencing analysis suggests that these surviving epithelial strands are formed by cells in the lower part of the hair follicle. These findings emphasize the importance of the regression phase in hair follicle regeneration and establish VDR as a regulator of the catagen stage.

Incidence of Hypophosphatemia After Intravenous Administration of Iron: A Matching-Adjusted Indirect Comparison of Data from Japanese Randomized Controlled Trials.

INTRODUCTION: Intravenous (IV) administration of iron is considered a safe and efficacious treatment for iron deficiency anemia (IDA), recommended in patients requiring rapid replenishment of iron, or intolerant or unresponsive to oral administration of iron. Recent randomized controlled trials (RCTs) have shown high incidence of hypophosphatemia after administration of two IV iron preparations: saccharated ferric oxide (SFO) and ferric carboxymaltose (FCM). The present study aimed to conduct matching-adjusted indirect comparison (MAIC) of hypophosphatemia incidence with these iron formulations and ferric derisomaltose (FDI) based on data from head-to-head RCTs conducted in Japan. METHODS: A MAIC of hypophosphatemia incidence was conducted on the basis of data from two head-to-head RCTs. The relative odds of hypophosphatemia with FDI versus SFO were obtained from patient-level data from a recent RCT and adjusted for cumulative iron dose, while parametric models of serum phosphate levels from a separate RCT were used to estimate the relative odds of hypophosphatemia with FCM with SFO. An anchored MAIC was then conducted comparing FDI with FCM. RESULTS: The adjusted odds of experiencing hypophosphatemia were significantly lower with FDI than SFO [odds ratio (OR) of 0.02; 95% confidence interval (CI) 0.01-0.05]. The parametric models of serum phosphate from the RCT comparing FCM with SFO provided an estimated OR of 1.17 for the incidence of hypophosphatemia with FCM versus SFO. Combining the two estimates in the MAIC showed that the odds of experiencing hypophosphatemia would be 52.5 (95% CI 27.7-99.4) times higher with FCM than FDI in patients with IDA associated with heavy menstrual bleeding in Japan. CONCLUSIONS: Direct comparison of patient-level data and a MAIC from two RCTs in Japanese patients with heavy menstrual bleeding indicated that hypophosphatemia is less frequent in patients treated with FDI than those with FCM or SFO. Results are in agreement with RCTs comparing FDI and FCM in patients with various etiologies conducted in the USA and Europe.

Single-cell RNA sequencing identifies Fgf23-expressing osteocytes in response to 1,25-dihydroxyvitamin D3 treatment.

Fibroblast growth factor 23 (FGF23), a hormone, mainly produced by osteocytes, regulates phosphate and vitamin D metabolism. By contrast, 1,25-dihydroxyvitamin D3, the active form of vitamin D, has been shown to enhance FGF23 production. While it is likely that osteocytes are heterogenous in terms of gene expression profiles, specific subpopulations of Fgf23-expressing osteocytes have not been identified. Single-cell RNA sequencing (scRNA-seq) technology can characterize the transcriptome of an individual cell. Recently, scRNA-seq has been used for bone tissue analysis. However, owing to technical difficulties associated with isolation of osteocytes, studies using scRNA-seq analysis to characterize FGF23-producing osteocytes are lacking. In this study, we characterized osteocytes secreting FGF23 from murine femurs in response to calcitriol (1,25-dihydroxyvitamin D3) using scRNA-seq. We first detected Dmp1, Mepe, and Phex expression in murine osteocytes by in situ hybridization and used these as marker genes of osteocytes. After decalcification, enzyme digestion, and removal of CD45+ cells, femoral bone cells were subjected to scRNA-seq. We identified cell clusters containing osteocytes using marker gene expression. While Fgf23 expression was observed in some osteocytes isolated from femurs of calcitriol-injected mice, no Fgf23 expression was detected in untreated mice. In addition, the expression of several genes which are known to be changed after 1,25-dihydroxyvitamin D3 treatment such as Ccnd2, Fn1, Igfbp7, Pdgfa, and Timp1 was also affected by calcitriol treatment in Fgf23-expressing osteocytes, but not in those lacking Fgf23 expression, even after calcitriol administration. Furthermore, box-and-whisker plots indicated that Fgf23 expression was observed in osteocytes with higher expression levels of the Fam20c, Dmp1, and Phex genes, whose inactivating mutations have been shown to cause FGF23-related hypophosphatemic diseases. These results indicate that osteocytes are heterogeneous with respect to their responsiveness to 1,25-dihydroxyvitamin D3, and sensitivity to 1,25-dihydroxyvitamin D3 is one of the characteristics of osteocytes with Fgf23 expression. It is likely that there is a subpopulation of osteocytes expressing several genes, including Fgf23, involved in phosphate metabolism.

Global guidance for the recognition, diagnosis, and management of tumor-induced osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by mesenchymal tumors that secrete fibroblast growth factor 23 (FGF23). Patients present with progressive bone pain, muscle weakness, and fragility fractures. TIO is characterized by hypophosphatemia, excess renal phosphate excretion, and low/inappropriately normal 1,25-dihydroxyvitamin D (1,25(OH)2 D) levels. Rarity and enigmatic clinical presentation of TIO contribute to limited awareness among the medical community. Accordingly, appropriate diagnostic tests may not be requested, leading to delayed diagnosis and poorer patient outcomes. We have developed a global guidance document to improve the knowledge of TIO in the medical community, enabling the recognition of patients with TIO and appropriate referral. We provide recommendations aiding diagnosis, referral, and treatment, helping promote a global standard of patient management. We reviewed the literature and conducted a three-round Delphi survey of TIO experts. Statements were drafted based on published evidence and expert opinions (≥70% consensus required for final recommendations). Serum phosphate should be measured in patients presenting with chronic muscle pain or weakness, fragility fractures, or bone pain. Physical examination should establish features of myopathy and identify masses that could be causative tumors. Priority laboratory evaluations should include urine/serum phosphate and creatinine to assess renal tubular reabsorption of phosphate and TmP/GFR, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, 1,25(OH)2 D, and FGF23. Patients with the clinical/biochemical suspicion of TIO should be referred to a specialist for diagnosis confirmation, and functional imaging should be used to localize causative tumor(s). Recommended treatment is tumor resection or, with unresectable/unidentifiable tumors, phosphate salts plus active vitamin D, or burosumab.

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.

Tumor-induced Osteomalacia: A Comprehensive Review.

Tumor-induced osteomalacia (TIO) is an ultrarare paraneoplastic syndrome due to overproduction of fibroblast growth factor 23 (FGF23), with profound effects on patient morbidity. TIO is an underdiagnosed disease, whose awareness should be increased among physicians for timely and proper management of patients. Symptoms reported by patients with TIO are usually nonspecific, thus rendering the diagnosis elusive, with an initial misdiagnosis rate of more than 95%. Biochemical features of TIO are represented by hypophosphatemia, increased or inappropriately normal levels of FGF23, and low to low normal circulating 1,25-dihydroxyvitamin D (1,25(OH)2D). Phosphaturic mesenchymal tumors are the pathological entities underlying TIO in most affected patients. There is now evidence that FN1-FGFR1 and FN1-FGF1 fusion genes are present in about half of tumors causing this paraneoplastic syndrome. Tumors causing TIO are small and grow slowly. They can occur in all parts of the body from head to toe with similar prevalence in soft tissue and bone. There are a number of functional and anatomical imaging techniques used for tumor localization; 68Ga DOTA-based technologies have better sensitivity. Surgery is the treatment of choice; several medical treatments are now available in case of inability to locate the tumor or in case of incomplete excision.

Prevalence of Pseudohypoparathyroidism and Nonsurgical Hypoparathyroidism in Japan in 2017: A Nationwide Survey.

BACKGROUND: Pseudohypoparathyroidism (PHP) and nonsurgical hypoparathyroidism (NS-HypoPT) are rare diseases with hypocalcemia, hyperphosphatemia, and high and low parathyroid hormone levels, respectively. In Japan, over 20 years have passed since the last survey on these diseases. We carried out a nationwide cross-sectional survey to estimate the prevalence of these diseases in 2018. METHODS: We conducted a nationwide mail-based survey targeting hospitals in 2018. From a total of 13,156 departments throughout Japan, including internal medicine, pediatrics, neurology, and psychiatry, 3,501 (27%) departments were selected using a stratified random sampling method. We asked each included department to report the number of patients with PHP and NS-HypoPT in 2017. RESULTS: The overall survey response rate was 52.0% (1,807 departments). The estimated number of patients with PHP and NS-HypoPT was 1,484 (95% confidence interval [CI], 1,143-1,825) and 2,304 (95% CI, 1,189-3,419), respectively; the prevalence per 100,000 population was 1.2 and 1.8, respectively. CONCLUSION: In this study, we generated estimates of the national prevalence of PHP and NS-HypoPT in Japan during 2017, which were found to be higher than those previously reported.

Combined treatment by burosumab and a calcimimetic can ameliorate hypophosphatemia due to excessive actions of FGF23 and PTH in adult XLH with tertiary hyperparathyroidism: A case report.

Introduction: X-linked hypophosphatemia (XLH) is the most prevalent type of heritable fibroblast growth factor 23 (FGF23)-related hypophosphatemic rickets. Recently, anti-FGF23 antibody, burosumab, has become clinically available. We herein report a patient with adult XLH and tertiary hyperparathyroidism. Case presentation: The serum phosphate level and tubular maximum reabsorption of phosphate per glomerular filtration rate (TmP/GFR) remained low, despite burosumab treatment. While the influence of the relationship between FGF23 and parathyroid hormone (PTH) on the phosphaturic effect is unclear, it was considered that a high level of PTH due to tertiary hyperparathyroidism remains to suppress renal phosphate reabsorption. A calcimimetic, evocalcet, increased the serum phosphate level and TmP/GFR. Discussion and conclusion: Therefore, it is important to evaluate the presence of secondary-tertiary hyperparathyroidism in patients whose serum phosphate level does not increase with burosumab treatment.

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.

Osteoblast/osteocyte-derived interleukin-11 regulates osteogenesis and systemic adipogenesis.

Exercise results in mechanical loading of the bone and stimulates energy expenditure in the adipose tissue. It is therefore likely that the bone secretes factors to communicate with adipose tissue in response to mechanical loading. Interleukin (IL)-11 is known to be expressed in the bone, it is upregulated by mechanical loading, enhances osteogenesis and suppresses adipogenesis. Here, we show that systemic IL-11 deletion (IL-11-/-) results in reduced bone mass, suppressed bone formation response to mechanical loading, enhanced expression of Wnt inhibitors, and suppressed Wnt signaling. At the same time, the enhancement of bone resorption by mechanical unloading was unaffected. Unexpectedly, IL-11-/- mice have increased systemic adiposity and glucose intolerance. Osteoblast/osteocyte-specific IL-11 deletion in osteocalcin-Cre;IL-11fl/fl mice have reduced serum IL-11 levels, blunted bone formation under mechanical loading, and increased systemic adiposity similar to IL-11-/- mice. Adipocyte-specific IL-11 deletion in adiponectin-Cre;IL-11fl/fl did not exhibit any abnormalities. We demonstrate that osteoblast/osteocyte-derived IL-11 controls both osteogenesis and systemic adiposity in response to mechanical loading, an important insight for our understanding of osteoporosis and metabolic syndromes.

An attempt to create a treatment algorithm of central adrenal insufficiency using CRH test, DHEA-S and clinical evaluation.

Objective : To examine diagnostic performance of corticotropin-releasing hormone (CRH) test combined with baseline dehydroepiandrosterone sulfate (DHEA-S) in patients with a suspect of central adrenal insufficiency. Methods : Patients (n=215) requiring daily or intermittent hydrocortisone replacement, or no replacement were retrospectively checked with their peak cortisol after CRH test and baseline DHEA-S. Results :  None of 106 patients with the peak cortisol ≥ 17.5 µg / dL after CRH test required replacement, and all 64 patients with the peak cortisol < 10.0 µg / dL required daily replacement. Among 8 patients with 10.0 µg / dL ≤ the peak cortisol < 17.5 µg / dL and baseline DHEA-S below the reference range, 6 patients required daily replacement and 1 patient was under intermittent replacement. Among 37 patients with 10.0 µg / dL ≤ the peak cortisol < 17.5 µg / dL and baseline DHEA-S within the reference range, 10 and 6 patients were under intermittent and daily replacement, respectively. Conclusions : No patients with the peak cortisol ≥ 17.5 µg / dL required hydrocortisone replacement, and all patients with the peak cortisol below 10.0 µg / dL required daily replacement. Careful clinical evaluation was required to determine requirement for replacement in patients with 10.0 µg / dL ≤ the peak cortisol < 17.5 µg / dL even in combination with baseline DHEA-S. J. Med. Invest. 69 : 287-293, August, 2022.