Category Ranking
98%
Total Visits
921
Avg Visit Duration
2 minutes
Citations
20
Article Abstract
JTT-305/MK-5442 is a calcium-sensing receptor (CaSR) allosteric antagonist being investigated for the treatment of osteoporosis. JTT-305/MK-5442 binds to CaSRs, thus preventing receptor activation by Ca(2+) . In the parathyroid gland, this results in the release of parathyroid hormone (PTH). Sharp spikes in PTH secretion followed by rapid returns to baseline are associated with bone formation, whereas sustained elevation in PTH is associated with bone resorption. We have developed a semimechanistic, nonpopulation model of the time-course relationship between JTT-305/MK-5442 and whole plasma PTH concentrations to describe both the secretion of PTH and the kinetics of its return to baseline levels. We obtained mean concentration data for JTT-305/MK-5442 and whole PTH from a multiple dose study in U.S. postmenopausal women at doses of 5, 10, 15, and 20 mg. We hypothesized that PTH is released from two separate sources: a reservoir that is released rapidly (within minutes) in response to reduction in Ca(2+) binding, and a second source released more slowly following hours of reduced Ca(2+) binding. We modeled the release rates of these reservoirs as maximum pharmacologic effect (Emax ) functions of JTT-305/MK-5442 concentration. Our model describes both the dose-dependence of PTH time of occurrence for maximum drug concentration (Tmax ) and maximum concentration of drug (Cmax ), and the extent and duration of the observed nonmonotonic return of PTH to baseline levels following JTT-305/MK-5442 administration.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1002/jbmr.1900 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Structure-Encoded Location Biased Signaling in a Class B GPCR: Focus on the PTH Type 1 Receptor.
Handb Exp Pharmacol
September 2025
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Research conducted over the last 15 years indicates that cAMP is generated not just from the plasma membrane but also from intracellular compartments, particularly in endosomes, where receptors are redistributed during the endocytosis process. This review centers on the parathyroid hormone type 1 receptor (PTHR) as a model for a peptide hormone GPCRs that generates cAMP from various locations with distinct duration and pharmacological effectiveness. We discuss how structural dynamics simulations aid in designing ligands that induce cAMP location bias, ultimately answering how the spatiotemporal generation of cAMP affects pharmacological responses mediated by the PTHR.
View Article and Find Full Text PDFThe cellular effect of intermittent PTH treatment on bone remodeling and modeling in humans-a histomorphometry centered scoping review.
Osteoporos Int
September 2025
Molecular Bone Histology Lab, Research Unit of Pathology, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
Intermittent PTH treatment has been used as both an osteoanabolic treatment in osteoporosis and a hormone replacement in hypoparathyroidism for many years. This scoping review compiles and reinterprets studies using histomorphometry supported by bone turnover markers to investigate the elusive cellular effect of intermittent PTH treatment locally within the bone, while illuminating knowledge gaps. Intermittent PTH increases both osteoclast and osteoblast activity within the first 6 months of treatment.
View Article and Find Full Text PDFA presentation of brown tumor in a patient with parathyroid adenoma and end-stage renal disease: A case report.
Medicine (Baltimore)
September 2025
Department of Internal Medicine, Lahore General Hospital, Lahore, Punjab, Pakistan.
Rationale: Brown tumor (osteitis fibrosa cystica) is a benign bone lesion associated with hyperparathyroidism that can affect multiple bones in patients with end-stage renal disease (ESRD).
Patient Concerns: We present the case of a 32-year-old female with ESRD on maintenance hemodialysis who experienced body aches, muscle weakness, constipation, and mood swings for 3 months.
Diagnoses: Initial tests revealed elevated parathyroid hormone (PTH), serum calcium, and phosphorus levels.
The Application of Assay- and Age-Specific Parathyroid Hormone (PTH) Reference Intervals Decreases the Diagnosis of Normocalcaemic Primary Hyperparathyroidism and Improves Diagnostic Concordance of PTH Assays.
Horm Metab Res
September 2025
Clinical Biochemistry, The Royal Wolverhampton NHS Trust, Black Country Pathology Services, Wolverhampton, United Kingdom of Great Britain and Northern Ireland.
Parathyroid hormone (PTH) assays are not standardized and therefore PTH results are interpreted using manufacturer-provided assay-specific reference intervals. Assay-specific PTH reference intervals, however, do not account for between-assay differences and lead to discordance in the diagnosis of normocalcaemic primary hyperparathyroidism (NCPHPT). PTH increases with age independent of vitamin D, renal function, phosphate and ionized calcium.
View Article and Find Full Text PDFA study of tertiary hyperparathyroidism.
Ir J Med Sci
September 2025
Sri Venkateswara Institute of Medical Sciences, Tirupati, India.
Introduction: Information on tertiary hyperparathyroidism (THPTH) among chronic kidney disease (CKD) patients on haemodialysis in developing countries such as India is limited, and the mortality among them remains a query.
Materials And Methods: This was a prospective cohort study conducted in at a tertiary care centre from June 2017 to June 2022. The index of suspicion for tertiary hyperparathyroidism was when investigations revealed high serum calcium and high alkaline phosphatase along with new onset of body aches, joint pains, and difficulty in walking.