Action Of Parathyroid Hormone Research Articles

Using machine learning models for predicting monthly iPTH levels in hemodialysis patients

Background and Objective: Intact parathyroid hormone (iPTH), also known as active parathyroid hormone, is an important indicator commonly for monitoring secondary hyperparathyroidism (SHPT) in patients undergoing hemodialysis. The aim of this study was to use machine learning (ML) models to predict monthly iPTH levels in patients undergoing hemodialysis.Methods: We conducted a retrospective study on patients undergoing regular hemodialysis. Patients’ blood examinations data was collected from Taiwan Society of Nephrology – Kidney Dialysis, Transplantation (TSN-KiDiT) registration system, and patients’ medications data was collected from Pingtung Christian Hospital (PTCH), Taiwan. We used five different ML models to classify patients into three distinct categories based on their iPTH levels: iPTH < 150, iPTH ≥ 150 & iPTH < 600, and iPTH ≥ 600(pg/ml).Results: We ultimately included 1,351 patients in our study and processed the data in four different ways. These methods varied based on the duration of the data (either using data from just one month or continuously over three months) and the number of features used (either all 52 features or only 20 most important features identified by SHapley Additive exPlanations (SHAP) analysis). The XGBoost model, using data from a continuous three-month period and all available features, yielded the best Weighted AUROC (0.922).Conclusions: ML is highly effective in predicting iPTH levels in hemodialysis patients, notably accurate for those with iPTH over 600 pg/ml. This method enables early identification of high-risk patients, reducing reliance on retrospective blood test assessments. Future research should focus on advancing explainable AI methods to foster clinicians' trust, and developing adaptable ML frameworks that could seamlessly integrate with existing healthcare systems.

MBX 2109, a Once-Weekly Parathyroid Hormone Replacement Therapy Prodrug: Phase 1, First-in-Human, Randomized Trial.

Hypoparathyroidism denotes parathyroid hormone (PTH) deficiency and impaired mineral metabolism. MBX 2109, a novel prodrug yielding a biologically active PTH peptide agonist (PTH[1-32], extended by a fatty acylated Lys33), is being developed as a long-acting, once-weekly PTH replacement therapy. Here, we report the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of MBX 2109 in healthy volunteers. This phase 1, randomized, double-blind, placebo-controlled, multiple ascending-dose study (NCT05158335) enrolled healthy adults, who were randomized 4:1 to receive MBX 2109 (200, 400, 600, and 900 μg; n = 8) or placebo (n = 2) by subcutaneous administration once weekly for 4 doses (days 1, 8, 15, and 22). The primary endpoint was safety and tolerability. Key secondary endpoints were PK and PD. Overall, 40 participants (MBX 2109 n = 32, placebo n = 8) were randomized (mean age, 43.3 years; 22.5% female). Treatment-emergent adverse events (TEAEs) occurred in 50%-88% of MBX 2109 groups and in 25% of placebo participants. In the MBX 2109 groups, no severe or serious TEAEs were observed. Injection-site reaction was the most common treatment-related TEAE. The half-lives were 79-95 hours for MBX 2109 and 184-213 hours for the fatty-acylated biologically active PTH peptide, which showed dose- and time-dependent exposure increases. The sustained-action PTH prodrug MBX 2109 was well tolerated with no unexpected, off-target safety issues. The long half-life and flat exposure profile of MBX 2109's biologically active PTH agonist supports once-weekly administration. MBX 2109 doses were identified for future studies.

Modulation of Serum Metabolic Profiles by Bifidobacterium breve BBr60 in Obesity: A Randomized Controlled Trial.

Obesity, a prevalent metabolic disorder in youth, leads to complications and economic strain. Gut dysbiosis significantly contributes to obesity and metabolic issues. Bifidobacterium breve, a probiotic strain, may help regulate gut dysbiosis and benefit obese individuals. However, more research is needed on its effect on serum metabolism. A total of 75 overweight or obese young adults (aged 19-45) participated in the current study, and were randomly divided into probiotic and placebo groups using a random number table. Both groups received dietary guidance and underwent twelve weeks of intervention with either oral Bifidobacterium breve BBr60 (BBr60) or a placebo. After the intervention, collection and analysis of fasting serum samples were conducted using mass spectrometry coupled with liquid chromatography. Analyses of associations were conducted in order to determine the correlations between key serum metabolites and clinical obesity indicators, aiming to understand the influence of BBr60. Due to 10 participants dropping out for personal reasons, the study included 32 and 33 participants in the placebo and the BBr60 groups, respectively. The BBr60 intervention significantly regulated 134 serum metabolites and influenced crucial metabolic pathways in obesity management (p < 0.05), including ascorbate and aldarate metabolism for oxidative stress reduction, cholesterol metabolism for lipid regulation, parathyroid hormone synthesis, secretion and action for the endocrine system, oxidative phosphorylation for enhanced energy efficiency, and glycolysis/gluconeogenesis for glucose metabolism. Analysis showed a positive relationship between fasting blood glucose (FBG), aspartate aminotransferase (AST), total protein (TP), and the content of 5-Methyl DL-glutamate (p < 0.05). Similarly, body mass index (BMI), weight, and body fat percentage (BFP) were positively linked to serum metabolites (1-Hydroxycyclohexyl) acetic acid, and 5-Oxooctanoic acid (p < 0.05). Significant associations of AST levels with key serum metabolites in cholesterol metabolism pathways further suggest BBr60's potential to improve liver function and overall metabolic health in overweight or obese individuals. These findings support BBr60's effectiveness in modulating serum metabolic profiles and suggest it may improve liver function and BMI in overweight or obese individuals by regulating key serum metabolites.

Multiple Machine Learning Identifies Key Gene PHLDA1 Suppressing NAFLD Progression.

Non-alcoholic fatty liver disease (NAFLD) poses a serious global health threat, with its progression mechanisms not yet fully understood. While several molecular markers for NAFLD have been developed in recent years, a lack of robust evidence hampers their clinical application. Therefore, identifying novel and potent biomarkers would directly aid in the prediction, prevention, and personalized treatment of NAFLD. We downloaded NAFLD-related datasets from the Gene Expression Omnibus (GEO). Differential expression analysis and functional analysis were initially conducted. Subsequently, Weighted Gene Co-expression Network Analysis (WGCNA) and multiple machine learning strategies were employed to screen and identify key genes, and the diagnostic value was assessed using Receiver Operating Characteristic (ROC) analysis. We then explored the relationship between genes and immune cells using transcriptome data and single-cell RNA sequencing (scRNA-seq) data. Finally, we validated our findings in cell and mouse NAFLD models. We obtained 23 overlapping differentially expressed genes (DEGs) across three NAFLD datasets. Enrichment analysis revealed that DEGs were associated with Apoptosis, Parathyroid hormone synthesis, secretion and action, Colorectal cancer, p53 signaling pathway, and Biosynthesis of unsaturated fatty acids. After employing machine learning strategies, we identified one gene, pleckstrin homology like domain family A member 1 (PHLDA1), downregulated in NAFLD and showing high diagnostic accuracy. CIBERSORT analysis revealed significant associations of PHLDA1 with various immune cells. Single-cell data analysis demonstrated downregulation of PHLDA1 in NAFLD, with PHLDA1 exhibiting a significant negative correlation with macrophages. Furthermore, we found PHLDA1 to be downregulated in an in vitro hepatic steatosis cell model, and overexpression of PHLDA1 significantly reduced lipid accumulation, as well as the expression of key molecules involved in hepatic lipogenesis and fatty acid uptake, such as FASN, SCD-1, and CD36. Additionally, gene set enrichment analysis (GSEA) pathway enrichment analysis suggested that PHLDA1 may influence NAFLD progression through pathways such as Cytokine Cytokine Receptor Interaction, Ecm Receptor Interaction, Parkinson's Disease, and Ribosome pathways. Our conclusions were further validated in a mouse model of NAFLD. Our study reveals that PHLDA1 inhibits the progression of NAFLD, as overexpression of PHLDA1 significantly reduces lipid accumulation in cells and markedly decreases the expression of key molecules involved in liver lipogenesis and fatty acid uptake. Therefore, PHLDA1 may emerge as a novel potential target for future prediction, diagnosis, and targeted prevention of NAFLD.

Transcriptome analysis to explore the mechanism of downregulated TNIK influencing the effect of risperidone.

Risperidone is one of the most reliable and effective antipsychotics for schizophrenia treatment. However, the mechanism of action of risperidone is not yet fully understood. Traf2 and Nck-interacting protein kinase (TNIK), a schizophrenia susceptibility gene, is associated with risperidone treatment response. Our previous in vitro experiments confirmed that downregulated TNIK affected the effect of risperidone on downstream targets. However, the effect of downregulated TNIK on risperidone-induced molecular expression remains to be further explored. Transcriptome analysis was performed on U251 cells subjected to risperidone, TNIK siRNA, and no treatment, respectively. Compared to the no-treatment group, two groups of DEGs were screened out and then intersected with the schizophrenia-related genes to screen the cross-talk genes. Those DEGs were analyzed using GO and KEGG. STRING and Cytoscape were used to construct a protein-protein interaction (PPI) network for the cross-talk gene. The results showed that the parathyroid hormone synthesis, secretion, and action were significantly enriched after risperidone treatment. Downregulated TNIK could have an impact on the collagen-containing extracellular matrix, signaling receptor activator activity, and PI3K-Akt signaling pathway. Interestingly, bone mineralization function and calcium signaling pathway were enriched in the cross-talk genes. Additionally, FGFR2, FGF1, and FGFR might be the potential targets for TNIK affecting the effects of risperidone. The study indicated that risperidone primarily influences functions and/or pathways associated with bone metabolism, potentially contributing to the adverse effect of osteoporosis. Our study may offer a novel perspective on investigating the mechanisms underlying the adverse effects of risperidone.

Metabolic signatures and risk of sarcopenia in suburb-dwelling older individuals by LC-MS-based untargeted metabonomics.

Untargeted metabonomics has provided new insight into the pathogenesis of sarcopenia. In this study, we explored plasma metabolic signatures linked to a heightened risk of sarcopenia in a cohort study by LC-MS-based untargeted metabonomics. In this nested case-control study from the Adult Physical Fitness and Health Cohort Study (APFHCS), we collected blood plasma samples from 30 new-onset sarcopenia subjects (mean age 73.2 ± 5.6 years) and 30 healthy controls (mean age 74.2 ± 4.6 years) matched by age, sex, BMI, lifestyle, and comorbidities. An untargeted metabolomics methodology was employed to discern the metabolomic profile alterations present in individuals exhibiting newly diagnosed sarcopenia. In comparing individuals with new-onset sarcopenia to normal controls, a comprehensive analysis using liquid chromatography-mass spectrometry (LC-MS) identified a total of 62 metabolites, predominantly comprising lipids, lipid-like molecules, organic acids, and derivatives. Receiver operating characteristic (ROC) curve analysis indicated that the three metabolites hypoxanthine (AUC=0.819, 95% CI=0.711-0.927), L-2-amino-3-oxobutanoic acid (AUC=0.733, 95% CI=0.598-0.868) and PC(14:0/20:2(11Z,14Z)) (AUC= 0.717, 95% CI=0.587-0.846) had the highest areas under the curve. Then, these significant metabolites were observed to be notably enriched in four distinct metabolic pathways, namely, "purine metabolism"; "parathyroid hormone synthesis, secretion and action"; "choline metabolism in cancer"; and "tuberculosis". The current investigation elucidates the metabolic perturbations observed in individuals diagnosed with sarcopenia. The identified metabolites hold promise as potential biomarkers, offering avenues for exploring the underlying pathological mechanisms associated with sarcopenia.

Identification of blood exosomal metabolomic profiling for high-altitude cerebral edema

High-altitude cerebral edema (HACE) is a severe neurological condition that can occur at high altitudes. It is characterized by the accumulation of fluid in the brain, leading to a range of symptoms, including severe headache, confusion, loss of coordination, and even coma and death. Exosomes play a crucial role in intercellular communication, and their contents have been found to change in various diseases. This study analyzed the metabolomic characteristics of blood exosomes from HACE patients compared to those from healthy controls (HCs) with the aim of identifying specific metabolites or metabolic pathways associated with the development of HACE conditions. A total of 21 HACE patients and 21 healthy controls were recruited for this study. Comprehensive metabolomic profiling of the serum exosome samples was conducted using ultraperformance liquid chromatography–tandem mass spectrometry (UPLC‒MS/MS). Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed to identify the metabolic pathways affected in HACE patients. Twenty-six metabolites, including ( +)-camphoric acid, choline, adenosine, adenosine 5′-monophosphate, deoxyguanosine 5′-monophosphate, guanosine, and hypoxanthine-9-β-D-arabinofuranoside, among others, exhibited significant changes in expression in HACE patients compared to HCs. Additionally, these differentially abundant metabolites were confirmed to be potential biomarkers for HACE. KEGG pathway enrichment analysis revealed several pathways that significantly affect energy metabolism regulation (such as purine metabolism, thermogenesis, and nucleotide metabolism), estrogen-related pathways (the estrogen signaling pathway, GnRH signaling pathway, and GnRH pathway), cyclic nucleotide signaling pathways (the cGMP-PKG signaling pathway and cAMP signaling pathway), and hormone synthesis and secretion pathways (renin secretion, parathyroid hormone synthesis, secretion and action, and aldosterone synthesis and secretion). In patients with HACE, adenosine, guanosine, and hypoxanthine-9-β-D-arabinofuranoside were negatively correlated with height. Deoxyguanosine 5′-monophosphate is negatively correlated with weight and BMI. Additionally, LPE (18:2/0:0) and pregnanetriol were positively correlated with age. This study identified potential biomarkers for HACE and provided valuable insights into the underlying metabolic mechanisms of this disease. These findings may lead to potential targets for early diagnosis and therapeutic intervention in HACE patients.

Preclinical development of EXT608, an investigational parathyroid hormone derivative with extended half-life for the treatment of hypoparathyroidism.

Hypoparathyroidism, a deficiency of parathyroid hormone (PTH), results in hypocalcemia, hyperphosphatemia, and hypercalciuria. The disease is poorly controlled by calcium and vitamin D supplements or native PTH(1-84) replacement therapy. A version of PTH is being developed using D-VITylation technology, whereby vitamin D is conjugated to a therapeutic peptide, which confers a long plasma half-life by virtue of binding to the abundant vitamin D binding protein (DBP). D-VITylation of PTH caused no reduction in activity at the PTHR1 receptor, and resulted in a plasma elimination half-life of 7-15h in rats and 24-32h in cynomolgus monkeys. Analysis of steady-state pharmacokinetics as a function of dose showed flat profiles with smaller peak:trough ratios at low doses, indicative of slower subcutaneous absorption. In thyroparathyroidectomized (TPTx) rats, PTH(1-34)-vitamin D conjugates restored serum calcium and phosphate levels into the normal range over the 24h dosing period, and increased bone turnover markers and reduced bone mineral density. Urinary calcium was initially elevated, but normalized by the end of treatment on day 27. In healthy monkeys, a single dose of PTH(1-34)-vitamin D conjugates elevated serum calcium levels above the normal range for a period of 24-48h while simultaneously reducing urinary calcium. Therefore, the lead compound, EXT608, is a promising candidate as a therapeutic that can truly mimic the endogenous activity of PTH and warrants further study in patients with hypoparathyroidism.

Interaction between p21-activated kinase 4 and β-catenin as a novel pathway for PTH-dependent osteoblast activation.

Parathyroid hormone (PTH) serves dual roles in bone metabolism, exhibiting both anabolic and catabolic effects. The anabolic properties of PTH have been utilized in the treatment of osteoporosis with proven efficacy in preventing fractures. Despite these benefits, PTH can be administered therapeutically for up to 2 years, and its use in patients with underlying malignancies remains a subject of ongoing debate. These considerations underscore the need for a more comprehensive understanding of the underlying mechanisms. p21-activated kinase 4 (PAK4) is involved in bone resorption and cancer-associated osteolysis; however, its role in osteoblast function and PTH action remains unknown. Therefore, in this study, we aimed to clarify the role of PAK4 in osteoblast function and its effects on PTH-induced anabolic activity. PAK4 enhanced MC3T3-E1 osteoblast viability and proliferation and upregulated cyclin D1 expression. PAK4 also augmented osteoblast differentiation, as indicated by increased mineralization found by alkaline phosphatase and Alizarin Red staining. Treatment with PTH (1-34), an active PTH fragment, stimulated PAK4 expression and phosphorylation in a protein kinase A-dependent manner. In addition, bone morphogenetic protein-2 (which is known to promote bone formation) increased phosphorylated PAK4 (p-PAK4) and PAK4 levels. PAK4 regulated the expression of both phosphorylated and total β-catenin, which are critical for osteoblast proliferation and differentiation. Moreover, p-PAK4 directly interacted with β-catenin, and disruption of β-catenin's binding to T-cell factor impaired PAK4- and PTH-induced osteoblast differentiation. Our findings elucidate the effect of PAK4 on enhancing bone formation in osteoblasts and its pivotal role in the anabolic activity of PTH mediated through its interaction with β-catenin. These insights improve the understanding of the mechanisms underlying PTH activity and should inform the development of more effective and safer osteoporosis treatments.

Normocalcemic hyperparathyroidism after successful parathyroidectomy for single parathyroid adenoma: Prevalence, etiological factors, predictive markers, treatment and evolution

Background and objectivePostparathyroidectomy normocalcemic hyperparathyroidism (PPNCHPPT) is a frequent situation for which we have no information in our country. The objective is to know our prevalence of PPNCHPPT, the associated etiological factors, the predictive markers, the treatment administered and the evolution. Patients and methodRetrospective observational cross-sectional study on 42 patients. Twelve patients with PPNCHPPT and 30 without PPNCHPPT are compared. ResultsHPPTNCPP prevalence: 28.6%. Etiological factors: vitamin D deficiency: 75%; bone remineralization: 16.7%; renal failure: 16.7%; hypercalciruria: 8.3%. No change in the set point of calcium-mediated parathormone (PTH) secretion was observed, but an increase in the preoperative PTH/albumin-corrected calcium (ACC) ratio was observed. Predictive markers: PTH/ACC ratio (AUC 0.947; sensitivity 100%, specificity 78.9%) and PTH (AUC 0.914; sensitivity 100%, specificity 73.7%) one week postparathyroidectomy. Evolution: follow-up 30 ± 16.3 months: 50% normalized PTH and 8.3% had recurrence of hyperparathyroidism. Patients with PPNCHPPT less frequently received preoperative treatment with bisphosphonates and postoperative treatment with calcium salts. ConclusionsThis is the first study in our country that demonstrates a mean prevalence of PPNCHPPT, mainly related to a vitamin D deficiency and a probable resistance to the action of PTH, which can be predicted by the PTH/ACC ratio and PTH a week post-intervention and often evolves normalizing the PTH. We disagree with the etiological effect of hypercalciuria and the change in the PTH/calcemia regulation set point, and we acknowledge the scant treatment administered with calcium salts in the postoperative period.

Lactiplantibacillus plantarum GL001 alleviates jejunal oxidative damage induced by intestinal ischemia-reperfusion injury by influencing jejunal tissue metabolism through the improvement of jejunal microbial composition

Intestinal ischemia-reperfusion (IIR) injury is associated with inflammation and oxidative stress, yet its precise mechanisms remain not fully understood. IIR injury is closely linked to the gut microbiota and its metabolites. The anti-inflammatory and antioxidant effects of Lactiplantibacillus plantarum are specific to IIR. In our study, we conducted a 30-day pre-treatment of SD rats with both a standard strain of Lactiplantibacillus plantarum and Lactiplantibacillus plantarum GL001. After a 7-day cessation of treatment, we induced an IIR injury model to investigate the mechanisms by which Lactiplantibacillus plantarum alleviates IIR damage. The results demonstrate that Lactiplantibacillus plantarum effectively mitigates the inflammatory and oxidative stress damage induced by IIR. Lactiplantibacillus plantarum GL001 can improve the gut microbiota by reducing the abundance of harmful bacteria and increasing the abundance of beneficial bacteria. In IIR intestinal tissue, the levels of secondary bile acids are elevated. The content of the bacterial metabolite Calcimycin increases. Annotations of metabolic pathways suggest that Lactiplantibacillus plantarum GL001 can alleviate IIR damage by modulating calcium-phosphorus homeostasis through the regulation of parathyroid hormone synthesis, secretion, and action. Microbiota-metabolite correlation analysis reveals a significant negative correlation between calcimycin and Lactonacillus and a significant positive correlation between calcimycin and Shigella. There is also a significant positive correlation between calcimycin and secondary bile acids. Lactiplantibacillus plantarum GL001 can alleviate oxidative damage induced by IIR through improvements in gut microbiota and intestinal tissue metabolism.

Hiperparatiroidismo normocalcémico tras paratiroidectomía exitosa por adenoma único paratiroideo: prevalencia, factores etiológicos, marcadores predictivos, tratamiento y evolución

Background and objectivePostparathyroidectomy normocalcemic hyperparathyroidism (PPNCHPPT) is a frequent situation for which we have no information in our country. The objective is to know our prevalence of PPNCHPPT, the associated etiological factors, the predictive markers, the treatment administered and the evolution. Patients and methodRetrospective observational cross-sectional study on 42 patients. Twelve patients with PPNCHPPT and 30 without PPNCHPPT are compared. ResultsHPPTNCPP prevalence: 28.6%. Etiological factors: vitamin D deficiency: 75%; bone remineralization: 16.7%; renal failure: 16.7%; hypercalciruria: 8.3%. No change in the set point of calcium-mediated parathormone (PTH) secretion was observed, but an increase in the preoperative PTH/albumin-corrected calcium (ACC) ratio was observed. Predictive markers: PTH/ACC ratio (AUC 0.947; sensitivity 100%, specificity 78.9%) and PTH (AUC 0.914; sensitivity 100%, specificity 73.7%) one week postparathyroidectomy. Evolution: follow-up 30±16.3 months: 50% normalized PTH and 8.3% had recurrence of hyperparathyroidism. Patients with PPNCHPPT less frequently received preoperative treatment with bisphosphonates and postoperative treatment with calcium salts. ConclusionsThis is the first study in our country that demonstrates a mean prevalence of PPNCHPPT, mainly related to a vitamin D deficiency and a probable resistance to the action of PTH, which can be predicted by the PTH/ACC ratio and PTH a week post-intervention and often evolves normalizing the PTH. We disagree with the etiological effect of hypercalciuria and the change in the PTH/calcemia regulation set point, and we acknowledge the scant treatment administered with calcium salts in the postoperative period.

SAT182 Effects Of An Orally Bioavailable Nonpeptide Parathyroid Hormone Receptor Type 1 (PTH1R) Antagonist In Rodent Models Of Primary Hyperparathyroidism (PHPT)

Abstract Disclosure: A.S. Antwan: Employee; Self; Crinetics Pharmaceuticals. E. Rico-Bautista: Employee; Self; Crinetics Pharmaceuticals. J. Pontillo: Employee; Self; Crinetics Pharmaceuticals. S. Wang: Employee; Self; Crinetics Pharmaceuticals. M. Johns: Employee; Self; Crinetics Pharmaceuticals. B. Ramms: Employee; Self; Crinetics Pharmaceuticals. M.A. Fowler: Employee; Self; Crinetics Pharmaceuticals. J.B. Nguyen: Employee; Self; Crinetics. A.A. Castellanos Gonzalez: Employee; Self; Crinetics. B. Fleck: Employee; Self; Crinetics Pharmaceuticals. K. Retting: Employee; Self; Crinetics Pharmaceuticals. D. Dalvie: Employee; Self; Crinetics Pharmaceuticals. S.F. Betz: Employee; Self; Crinetics Pharmaceuticals. S. Markison: Employee; Self; Crinetics Pharmaceuticals. Primary hyperparathyroidism (PHPT) is a condition resulting from an over-secretion of parathyroid hormone (PTH) from one or more overactive parathyroid glands. PTH is a peptide hormone that regulates blood calcium concentrations through effects on bone, intestines, and kidney. PTH acts on parathyroid hormone receptor type 1 (PTH1R) in the kidney to increase calcium reabsorption and block phosphate reabsorption. The loss of phosphate ions then causes an increase in ionized calcium in the blood and cAMP in the urine. At the bone, continuous PTH infusion stimulates osteoclast activity while inhibiting osteoblast activity, leading to breakdown of bone and release of calcium into the extracellular fluid. Conditions that cause excess PTH, such as PHPT, result in elevated concentrations of plasma calcium, increased bone loss, increased fracture risk, and higher susceptibility to kidney stone development. PHPT affects approximately 100,000 patients per year, but many patients are asymptomatic and remain undiagnosed. While a partial or total parathyroidectomy may be suitable for patients diagnosed with severe cases of PHPT, there are limited treatment options for those who do not meet the criteria or do not wish to undergo surgery. The goals for medicinal treatment are to normalize blood calcium levels and urinary calcium excretion, as well as increase bone mineral density to reduce fracture risk. Blocking PTH action directly via a potent PTH1R antagonist may provide an important new therapeutic mechanism to treat patients with PHPT. Using iterative medicinal chemistry and pharmacology, Crinetics has identified several potent and orally bioavailable PTH1R antagonists with good drug-like properties. Lead molecules were evaluated in vivo in preclinical rodent models for their ability to suppress the effects of excess PTH on serum calcium, bone turnover, and cAMP levels in the kidney. One of these compounds, ANT-5, was characterized as a potent negative allosteric modulator of both human and rat PTH1R. In rats, oral administration of ANT-5 dose-dependently suppressed PTH-induced hypercalcemia. ANT-5 also suppressed PTH-stimulated urinary cAMP in rats, indicating its ability to inhibit the actions of PTH in the kidney. We further evaluated the effect of ANT-5 in a rodent model of continuous PTH infusion-induced bone turnover. Once-daily oral administration of ANT-5 mitigated PTH-induced bone resorption, suggesting that inhibiting PTH1R may have beneficial clinical effects on bone density. The culmination of these studies has led to a subset of candidate molecules that are being evaluated in safety studies to identify the compound(s) suitable for evaluation in human clinical trials. Support: Crinetics Pharmaceuticals. Presentation: Saturday, June 17, 2023

OR29-01 Deleting Salt Inducible Kinases In Osteoprogenitor Cells Increases Trabecular Bone

Abstract Disclosure: G. Papaioannou: None. A. Morellato Alcantara: None. K. Strauss: None. H.M. Kronenberg: None. M.N. Wein: Other; Self; Radius Health, Inc, research funding and patent royalties, holds equity in and is a scientific advisory board member of Relation Therapeutics, consultant for AstraZeneca, Guidepoint LLC, and Aditum Bio. Introduction: Osteoblasts are continuously generated by the differentiation of skeletal progenitor cells. Osx positive cells are committed osteoprogenitors. Ebf3 positive cells are a group of bone marrow stromal cells marked by CXCL12 expression that are thought to contribute to osteoblasts in adult mice. Salt-inducible kinases (SIKs) are key kinases that control the skeletal actions of parathyroid hormone. We previously reported that deletion of SIK genes in osteoblasts/osteocytes (using Dmp1-Cre) or ubiquitously (using Ub-CreERt2) causes dramatic increases of trabecular bone and stromal cells. However, the specific osteoblast progenitor populations through which SIKs control bone homeostasis downstream of PTH signaling are still to be determined. Methods: SIK genes were deleted from Osx or Ebf3 positive cells in 3-day-old, 6- or 9-week-old mice using the CreERt2 (tamoxifen inducible) system. OsxCreERt2 mice were crossed with animals harboring floxed Sik2 and Sik3 genes. Ebf3CreERt2 mice were crossed with Sik1, Sik2, and Sik3 floxed mice. These mice also bear a tdTomato reporter that labels cells and their descendants upon Cre recombination. After sacrifice, tibiae were fixed in paraformaldehyde or formalin and decalcified in EDTA for frozen or paraffin sections respectively. Results: In OsxCreERt2; Sik2f/f;Sik3f/f;R26R-Tomato mice tamoxifen was injected at 6 weeks old or P3 and tibias were harvested 4 weeks later. In both cases there was a dramatic increase in trabecular bone mass, that filled a large part of the bone marrow, and an increase in stromal cells. Most of the osteoblasts and many of the stromal cells were tomato positive, indicating that they derive from the osteoprogenitors in which SIKs were deleted. In Ebf3CreERt2;Sik1f/f;Sik2f/f;Sik3f/f;R26R-Tomato mice, tamoxifen was injected at 9-weeks of age and tibiae examined 3 and 9 weeks later, or tamoxifen was given at 3 days of age and tibiae examined 4 weeks later. There were no obvious differences in H/E staining and no significant differences in the number or localization of cells labeled with tomato reporter. The number of tomato positive cells was small (compared to the OsxCreER model) at all ages examined. Some of these cells, were lining the bone, presumably becoming osteoblasts, but interestingly did not increase their number despite SIK deletion and in contrast with the OsxCreER model. Conclusion: Conditional deletion of SIK genes in Osx positive cells leads to a dramatic increase of trabecular bone and stromal cells in long bones suggesting a crucial role for SIKs in more committed osteoprogenitors and their descendants. The SIK pathway may not play a role in the subset of mesenchymal progenitor cells labeled with Ebf3CreERt2. Presentation: Sunday, June 18, 2023

A-042 Comparison of the Second-Generation Parathyroid Hormone Assays: ELSA-PTH and Alinity i Intact PTH

Abstract Background Measurement of parathyroid hormone (PTH) level is essential in diagnosing and treating hyper- and hypoparathyroidism. Because of the various presenting forms of PTH (biologically active full-length PTH and also PTH fragments) in the blood and the lack of standardization, there can be a difference in results between the assays even when the same assay generation is used. We compared the two second-generation PTH assays, ELSA-PTH and Alinity i Intact PTH, and evaluated the analytical performance of Alinity i Intact PTH, newly adopted in the laboratory. Methods For method comparison, 56 remnant samples of routinely ordered sera for the PTH test were collected. ESLA-PTH assay tested on Gamma-10 contains the anti-[39-84, amino acids] PTH antibody coated on the tube, which captures PTH in the sample and is measured by the radioactivity through the bound I125-labelled anti-[1-34] PTH antibody. Alinity i Intact PTH assay performed on Alinity i system uses the anti-[39-84] PTH antibody coated on a paramagnetic microparticle and is analyzed by the emitted light through the captured acridinium-labeled anti-[1-34] PTH antibody. The correlation between the two tests was evaluated. Additionally, precision, linearity, and reference range verification were analyzed to investigate the performance of the Alinity i Intact PTH assay. Results Of the 56 samples, 35 (62.5%) were requested by the Nephrology department for evaluating chronic kidney disease, 16 (28.6%) by the General surgery department during and after parathyroid and thyroid surgery, and 5 (8.9%) by other departments. 52.3% of the patients were female, and the median age was 61.5 years (interquartile range: 45.3–71). The median values of ELSA-PTH and Alinity i Intact PTH were 69.0 pg/mL and 101.9 pg/mL, respectively, and the PTH values of Alinity i Intact PTH were significantly higher (P &amp;lt; 0.0001) by the Wilcoxon test. The Pearson correlation coefficient (r) was 0.959, and the average difference between the two tests was 78.57 pg/mL. In Alinity i Intact PTH, the coefficient of variation obtained at each low (10.5 pg/mL), medium (66.6 pg/mL), high (254.6 pg/mL) levels were 1.9%, 2.4%, and 1.8% for repeatability, and 2.03%, 2.71%, and 2.65% for within-laboratory precision, respectively. Linearity was observed within the analytical measuring range of 3–3000 pg/mL. The reference range (15–68.3 pg/mL) recommended by the manufacturer was validated with 20 normal sera. Conclusion The PTH values of Alinity i Intact PTH were significantly higher than those of the ELSA-PTH, and both assays showed a strong correlation. Additionally, the Alinity i Intact PTH assay demonstrated acceptable analytical performance.

Literature Review: The Effect of Sun Exposure on Parathyroid Hormone Activity

Abstract:Indonesia is one of the tropical countries with year-round sunshine. This certainly allows Indonesians to be regularly exposed to the sun during daytime activities outside the home. Exposure to the sun has a significant impact on humans. To date, research on the prevalence of vitamin D deficiency, particularly in humans, has been rare. The purpose of this literature review is to provide the reader with information on the effects of sun exposure on parathyroid hormone levels. The method used to write this document is the literary criticism method. (LRA) with references taken from published or revoked (POP) databases published between 2010 and 2022. In this literature review, the keywords used include including sun, hormones, activity, vitamin D, parathyroid glands. Based on literature from a variety of research findings, it was found that sun exposure affects parathyroid hormone levels. Because vitamin D in sunlight is in the form of 1,25(OH)2D, it works with parathyroid hormone and calcitonin to maintain normal plasma calcium levels.

Replacing dietary sodium selenite with biogenic selenium nanoparticles improves the growth performance and gut health of early-weaned piglets

Selenium nanoparticles (SeNPs) are proposed as a safer and more effective selenium delivery system than sodium selenite (Na2SeO3). Here, we investigated the effects of replacing dietary Na2SeO3 with SeNPs synthesized by Lactobacillus casei ATCC 393 on the growth performance and gut health of early-weaned piglets. Seventy-two piglets (Duroc × Landrace × Large Yorkshire) weaned at 21 d of age were divided into the control group (basal diet containing 0.3 mg Se/kg from Na2SeO3) and SeNPs group (basal diet containing 0.3 mg Se/kg from SeNPs) during a 14-d feeding period. The results revealed that SeNPs supplementation increased the average daily gain (P = 0.022) and average daily feed intake (P = 0.033), reduced (P = 0.056) the diarrhea incidence, and improved (P = 0.013) the feed conversion ratio compared with Na2SeO3. Additionally, SeNPs increased jejunal microvilli height (P = 0.006) and alleviated the intestinal barrier dysfunction by upregulating (P < 0.05) the expression levels of mucin 2 and tight junction proteins, increasing (P < 0.05) Se availability, and maintaining mitochondrial structure and function, thereby improving antioxidant capacity and immunity. Furthermore, metabolomics showed that SeNPs can regulate lipid metabolism and participate in the synthesis, secretion and action of parathyroid hormone, proximal tubule bicarbonate reclamation and tricarboxylic acid cycle. Moreover, SeNPs increased (P < 0.05) the abundance of Holdemanella and the levels of acetate and propionate. Correlation analysis suggested that Holdemanella was closely associated with the regulatory effects of SeNPs on early-weaned piglets through participating in lipid metabolism. Overall, replacing dietary Na2SeO3 with biogenic SeNPs could be a potential nutritional intervention strategy to prevent early-weaning syndrome in piglets.

Site specific differences in vBMD and geometry in postmenopausal women with primary hyperparathyroidism.

Primary Hyperparathyroidism (PHPT) is associated with catabolic effects at both trabecular and cortical bone. Mechanical loading is one of the most important natural anabolic stimuli for bone at all ages. The present study was designed to assess the impact of PHPT on vBMD and bone geometry using peripheral quantitative computed tomography (pQCT) at the radius and tibia, sites with similar structural characteristics, but subject to different loading conditions. We evaluated the impact of PHPT on bone, by comparing the z-scores of volumetric Bone Mineral Density (vBMD) and indices of bone geometry simultaneously at the tibia and the radius by pQCT, skeletal sites with similar structure, but subject to different loading conditions. Forty-one postmenopausal women with PHPT and 79 controls, comprised the study group. At both trabecular and cortical sites, vBMD and bone geometry indices were significantly lower in patients compared with controls. In patients with PHPT, apart from a lower z-score for total vBMD (p = 0.01) at the radius, there was no other difference between the radius and the tibia at the trabecular sites. On the contrary, at cortical sites, the z-scores of cortical bone mineral content (p = 0.02), cortical vBMD (p = 0.01) and cortical cross-sectional area (p = 0.05) were significantly lower at the radius compared with the tibia, indicating that cortical bone at the weight bearing tibia might be less affected by the catabolic actions of continuous parathyroid hormone (PTH) exposure. PTH levels were positively associated with the difference in z-scores of cort BMD (r = 0.439, p < 0.01) indicating that in more severe cases, as expressed by higher PTH levels, the deleterious effects at the non-weight bearing radius might be accentuated. We found that in postmenopausal women with PHPT, both trabecular and cortical bone are adversely affected. However, at the weight bearing tibia as compared with the radius, the deleterious effects, especially on cortical bone, seem to be attenuated. NCT05426512, 21/06/2022, "retrospectively registered".

Nutrition recommendations for patients with pseudohypoparathyroidism

Pseudohypoparathyroidism (PHP) is a spectrum of diseases characterized by insensitivity of target tissues to the action of parathyroid hormone and, consequently, by the presence of hyperphosphatemia and hypocalcaemia of varying severity. Early-onset obesity is a feature of PHP type 1A.This article discusses the need to establish uniform criteria to guide the nutritional management of patients with PHP. A decrease in energy expenditure calls for an adjustment of the energy content of the diet. Reducing the intake of foods rich in inorganic phosphorus helps to manage hyperphosphataemia. Targeted nutrition should be part of the treatment plan of children and adolescents with PHP, since it contributes to modulating the calcium and phosphorus metabolism imbalances characteristic of these patients.

Recomendaciones nutricionales para pacientes con seudohipoparatiroidismo

Pseudohypoparathyroidism (PHP) is a spectrum of diseases characterized by insensitivity of target tissues to the action of parathyroid hormone and, consequently, by the presence of hyperphosphatemia and hypocalcaemia of varying severity. Early-onset obesity is a feature of PHP type 1A.This article discusses the need to establish uniform criteria to guide the nutritional management of patients with PHP. A decrease in energy expenditure calls for an adjustment of the energy content of the diet. Reducing the intake of foods rich in inorganic phosphorus helps manage hyperphosphataemia. Targeted nutrition should be part of the treatment plan of children and adolescents with PHP, since it contributes to modulating the calcium and phosphorus metabolism imbalances characteristic of these patients.