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Journal of Bone and Mineral Research :... Dec 2022The efficacy and safety of parathyroid hormone (PTH) therapy for managing long-term hypoparathyroidism is being evaluated in ongoing clinical trials. We undertook a... (Meta-Analysis)
Meta-Analysis
The efficacy and safety of parathyroid hormone (PTH) therapy for managing long-term hypoparathyroidism is being evaluated in ongoing clinical trials. We undertook a systematic review and meta-analysis of currently available randomized controlled trials to investigate the benefits and harms of PTH therapy and conventional therapy in the management of patients with chronic hypoparathyroidism. To identify eligible studies, published in English, we searched Embase, PubMed, and Cochrane CENTRAL from inception to May 2022. Two reviewers independently extracted data and assessed the risk of bias. We defined patients' important outcomes and used grading of recommendations, assessment, development, and evaluation (GRADE) to provide the structure for quantifying absolute effects and rating the quality of evidence. Seven randomized trials of 12 publications that enrolled a total of 386 patients proved eligible. The follow-up duration ranged from 1 to 36 months. Compared with conventional therapy, PTH therapy probably achieves a small improvement in physical health-related quality of life (mean difference [MD] 3.4, 95% confidence interval [CI] 1.5-5.3, minimally important difference 3.0, moderate certainty). PTH therapy results in more patients reaching 50% or greater reduction in the dose of active vitamin D and calcium (relative risk [RR] = 6.5, 95% CI 2.5-16.4, 385 more per 1000 patients, high certainty). PTH therapy may increase hypercalcemia (RR =2.4, 95% CI 1.2-5.04, low certainty). The findings may support the use of PTH therapy in patients with chronic hypoparathyroidism. Because of limitations of short duration and small sample size, evidence from randomized trials is limited regarding important benefits of PTH therapy compared with conventional therapy. Establishing such benefits will require further studies. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Topics: Humans; Hypercalcemia; Hypoparathyroidism; Parathyroid Hormone; Quality of Life; Vitamin D
PubMed: 36385517
DOI: 10.1002/jbmr.4676 -
Vitamins and Hormones 2022Parathyroid hormone (PTH) and PTH-related peptide (PTHrP) regulate extracellular phosphate and calcium homeostasis as well as bone remodeling. PTH is a classic endocrine... (Review)
Review
Parathyroid hormone (PTH) and PTH-related peptide (PTHrP) regulate extracellular phosphate and calcium homeostasis as well as bone remodeling. PTH is a classic endocrine peptide hormone whose synthesis and negative feedback by multiple factors control release from the parathyroid glands. PTHrP is ubiquitously expressed (pre- and postnatally) and acts in an autocrine/paracrine manner. This review considers the structural pharmacology and actions of PTH and PTHrP, biological consequences of inherited mutations, engineered analogs that illuminate similarities and differences in physiologic actions, and targeted therapeutic opportunities.
Topics: Humans; Parathyroid Hormone; Parathyroid Hormone-Related Protein
PubMed: 35953106
DOI: 10.1016/bs.vh.2022.03.001 -
American Journal of Physiology. Cell... Sep 2022The canonical model for G protein-coupled receptors (GPCRs) activation assumes that stimulation of heterotrimeric G protein signaling upon ligand binding occurs solely... (Review)
Review
The canonical model for G protein-coupled receptors (GPCRs) activation assumes that stimulation of heterotrimeric G protein signaling upon ligand binding occurs solely at the cell surface and that duration of the stimulation is transient to prevent overstimulation. In this model, GPCR signaling is turned-off by receptor phosphorylation via GPCR kinases (GRKs) and subsequent recruitment of β-arrestins, resulting in receptor internalization into endosomes. Internalized receptors can then recycle back to the cell surface or be trafficked to lysosomes for degradation. However, over the last decade, this model has been extended by discovering that some internalized GPCRs continue to signal via G proteins from endosomes. This is the case for the parathyroid hormone (PTH) type 1 receptor (PTHR), which engages on sustained cAMP signaling from endosomes upon PTH stimulation. Accumulative evidence shows that the location of signaling has an impact on the physiological effects of GPCR signaling. This mini-review discusses recent insights into the mechanisms of PTHR endosomal signaling and its physiological impact.
Topics: Arrestins; Cyclic AMP; Parathyroid Hormone; Receptor, Parathyroid Hormone, Type 1; Receptors, G-Protein-Coupled; Signal Transduction; beta-Arrestins
PubMed: 35912987
DOI: 10.1152/ajpcell.00452.2021 -
Acta Physiologica (Oxford, England) May 2023Central to the maintenance of calcium homeostasis is the regulated reabsorption of calcium along the nephron. To this end, parathyroid hormone (PTH) is released from the... (Review)
Review
Central to the maintenance of calcium homeostasis is the regulated reabsorption of calcium along the nephron. To this end, parathyroid hormone (PTH) is released from the parathyroid gland in response to lowered plasma calcium levels. This hormone acts through the PTH 1 receptor along the nephron to increase urinary phosphate excretion and decrease urinary calcium excretion. In the proximal tubule, PTH inhibits phosphate reabsorption by reducing the abundance of sodium phosphate cotransporters in the apical membrane. PTH likely decreases calcium reabsorption from the proximal tubule, by reducing the reabsorption of sodium, an event necessary for the paracellular movement of calcium across this segment. In the thick ascending limb (TAL), PTH increases calcium permeability and may increase the electrical driving force thereby increasing calcium reabsorption in the TAL. Finally, in the distal convolution, PTH acts to increase transcellular calcium reabsorption by increasing the activity and abundance of the apically expressed calcium channel TRPV5.
Topics: Calcium; Parathyroid Hormone; Phosphates; Kidney Tubules; Kidney Tubules, Proximal
PubMed: 36894509
DOI: 10.1111/apha.13959 -
Clinica Chimica Acta; International... Jan 2023Automated immunoassays used to evaluate parathyroid function are vulnerable to different types of interference, which can affect clinical practices. This review provides... (Review)
Review
Automated immunoassays used to evaluate parathyroid function are vulnerable to different types of interference, which can affect clinical practices. This review provides a detailed overview of the six main types of interference known to affect the measurement of parathyroid hormone (PTH): heterophilic antibodies, biotin, PTH fragments, oxidized PTH (oxPTH), phosphorylated PTH, and some preanalytical factors. Because the prevalence of some of these conditions has been reported to approach 11.7%, and the frequency of testing for parathyroid function is important, the scale of the problem might be tremendous. Potential interference in parathyroid function testing should always be suspected whenever clinical or biochemical discrepancies arise. Their identification typically relies on additional laboratory tests, including method comparison, serial dilution, blocking reagent studies, affinity adsorption, and polyethylene glycol precipitation. Moreover, some of these issues can be mitigated with the development of mass spectrometry. This review also evaluated the clinical impact of parathyroid interference on immunoassays, including misdiagnosis, inappropriate parathyroidectomy; and delay in receiving appropriate therapy. Hence, strong communication should be maintained between the clinician and laboratory to avoid such scenarios.
Topics: Humans; Parathyroid Hormone; Biotin; Indicators and Reagents; Immunoassay
PubMed: 36566956
DOI: 10.1016/j.cca.2022.12.022 -
Best Practice & Research. Clinical... Sep 2022Glucocorticoid use is ubiquitous and is associated with multiple adverse reactions. Among them, osteoporosis and bone fractures are of our concern. In this review, we... (Review)
Review
Glucocorticoid use is ubiquitous and is associated with multiple adverse reactions. Among them, osteoporosis and bone fractures are of our concern. In this review, we present current evidence on the effect of glucocorticoids on bone mineral density and the risk of fractures, the mechanisms underlying those effects, and the recommendations for monitoring and treating patients who take them. The bone mineral density of the lumbar spine and total hip is lower, and the risk of fractures is higher in glucocorticoid users than non-users. These effects have a rapid onset, are dose-dependent, and improve soon after discontinuation of glucocorticoids. They also appear to occur even with non-systemic routes of administration and with low doses. Glucocorticoids reduce bone mineral density by increasing osteoclast activity and decreasing osteoblast and osteocyte activity. Calcium metabolism and parathyroid hormone activity are less important than was initially thought. Treatment decisions are on risk stratification using clinical, radiographic, and prediction tools. Our armamentarium for the treatment and prevention of glucocorticoid-induced osteoporosis includes calcium and vitamin D, bisphosphonates, recombinant parathyroid hormone, monoclonal antibodies against receptor activator of nuclear factor kappa-B ligand, and hormone treatments.
Topics: Humans; Glucocorticoids; Calcium; Osteoporosis; Fractures, Bone; Bone Density; Parathyroid Hormone
PubMed: 36347775
DOI: 10.1016/j.berh.2022.101793 -
Handbook of Experimental Pharmacology 2020Parathyroid hormone (PTH), PTH-related peptide (PTHrP), PTHR, and their cognate G protein-coupled receptor play defining roles in the regulation of extracellular calcium... (Review)
Review
Parathyroid hormone (PTH), PTH-related peptide (PTHrP), PTHR, and their cognate G protein-coupled receptor play defining roles in the regulation of extracellular calcium and phosphate metabolism and in controlling skeletal growth and repair. Acting through complex signaling mechanisms that in many instances proceed in a tissue-specific manner, precise control of these processes is achieved. A variety of direct and indirect disease processes, along with genetic anomalies, can cause these schemes to become dysfunctional. Here, we review the basic components of this regulatory network and present both the well-established elements and emerging findings and concepts with the overall objective to provide a framework for understanding the elementary aspects of how PTH and PTHrP behave and as a call to encourage further investigation that will yield more comprehensive understanding of the physiological and pathological steps at play, with a goal toward novel therapeutic interventions.
Topics: Bone and Bones; Calcium; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Signal Transduction
PubMed: 32462362
DOI: 10.1007/164_2020_362 -
Deutsche Medizinische Wochenschrift... Feb 2020Calcium is pivotal for neuromuscular function, coagulation, and signal transduction. An imbalance of enteral calcium uptake, deposition in and resorption from bones, and...
Calcium is pivotal for neuromuscular function, coagulation, and signal transduction. An imbalance of enteral calcium uptake, deposition in and resorption from bones, and renal calcium elimination causes hypercalcemia. The dissociation between total serum calcium and ionized calcium has important implications in diagnosing hypercalcemia. The calcium sensing receptor (CaSR) regulates parathyroid hormone release and renal calcium reabsorption. Knowing the actions of the CaSR is important for diagnosing and treating patients with hyperparathyroidism. Diuretics can cause hypercalcemia, but also provide a clinical tool to lower serum calcium.
Topics: Calcium; Humans; Hypercalcemia; Parathyroid Hormone; Receptors, Calcium-Sensing
PubMed: 32018291
DOI: 10.1055/a-0851-5200 -
Annales D'endocrinologie Aug 2023Treatment of chronic hypoparathyroidism remains a therapeutic challenge. In three quarters of cases, this endocrine disorder arises as a consequence of neck surgery, but... (Review)
Review
Treatment of chronic hypoparathyroidism remains a therapeutic challenge. In three quarters of cases, this endocrine disorder arises as a consequence of neck surgery, but it can also present in other disease settings, for example, in rare genetic disorders. Conventional standard of care treatment is based on oral administration of calcium and vitamin D. However, a significant proportion of patients remain uncontrolled biochemically under this treatment, with persistent clinical symptoms that affect quality of life. Administration of parathyroid hormone (PTH) in more recent times has encountered the problem of the short half-life of the hormone, which necessitates multiple daily injections or continuous subcutaneous administration controlled by a pump. Recently, progress in understanding the pathophysiology of hypoparathyroidism has opened the possibility of new therapeutic approaches using longer-acting forms of PTH, PTH receptor analogs or, more recently, calcilytic agents. These are the subjects of current clinical trials, with encouraging results. However, their possible future use will depend on their long-term impacts on bone metabolism and renal function, which remain to be determined.
Topics: Humans; Quality of Life; Hypoparathyroidism; Parathyroid Hormone; Calcium; Vitamin D
PubMed: 37080533
DOI: 10.1016/j.ando.2023.04.001 -
Journal of Bone and Mineral Research :... Dec 2022The approach utilized a systematic review of the medical literature executed with specifically designed criteria that focused on the etiologies and pathogenesis of...
The approach utilized a systematic review of the medical literature executed with specifically designed criteria that focused on the etiologies and pathogenesis of hypoparathyroidism. Enhanced attention by endocrine surgeons to new knowledge about parathyroid gland viability are reviewed along with the role of intraoperative parathyroid hormone (ioPTH) monitoring during and after neck surgery. Nonsurgical etiologies account for a significant proportion of cases of hypoparathyroidism (~25%), and among them, genetic etiologies are key. Given the pervasive nature of PTH deficiency across multiple organ systems, a detailed review of the skeletal, renal, neuromuscular, and ocular complications is provided. The burden of illness on affected patients and their caregivers contributes to reduced quality of life and social costs for this chronic endocrinopathy. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Topics: Humans; Hypoparathyroidism; Parathyroid Hormone; Quality of Life; Parathyroid Glands
PubMed: 36153665
DOI: 10.1002/jbmr.4714