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Current Drug Safety May 2006Osteoporosis is characterized by low bone mineral density and deterioration in the microarchitecture of bone that increases its fracture vulnerability. The mainstay of... (Review)
Review
Osteoporosis is characterized by low bone mineral density and deterioration in the microarchitecture of bone that increases its fracture vulnerability. The mainstay of therapy for osteoporosis is anti-resorptive in mechanism. Parathyroid hormone (PTH) is the most recently approved anabolic agent for osteoporosis. The mechanism of PTH's skeleton anabolic action is composite involving pathways linked to common signalling peptides that affect gene osteoblast transcription. A number of animal studies and clinical trials have demonstrated that intermittent PTH administration induces anabolic effects on both cancellous and cortical bone, enhances bone mass and increases mechanical bone strength, increasing spine and hip bone mineral density and reducing fragility fractures. Preclinical studies investigating the effect of PTH on fracture healing show an increase in bone density and strength indicating an enhancement of this biological cascade. Preclinical and clinical safety assessments have revealed little evidence of toxic effects and there have been few reports of adverse events related to their use. An increase in osteosarcoma in rats probably is not prognostic of an equivalent possibility in humans. In summary, parathyroid hormone is a major advance in the treatment of osteoporosis. Additional studies addressing long-term clinical safety are needed. However the current evidence is very promising.
Topics: Animals; Bone Density; Bone Regeneration; Clinical Trials as Topic; Drug Evaluation, Preclinical; Female; Humans; Immunologic Factors; Male; Osteoporosis; Parathyroid Hormone
PubMed: 18690930
DOI: 10.2174/157488606776930571 -
Calcified Tissue International Jun 1998Most of the data on the anabolic effect of PTH have been obtained with hPTH(1-34). Studies have shown a marked increment in spinal bone mass. Most recently we have shown... (Review)
Review
Most of the data on the anabolic effect of PTH have been obtained with hPTH(1-34). Studies have shown a marked increment in spinal bone mass. Most recently we have shown that PTH and estrogen can be given together where there is increased total bone mineral and no loss of bone at any skeletal site. We have also shown the first reduction in vertebral deformity incidence due to PTH treatment.
Topics: Animals; Estrogens; Humans; Osteoporosis; Parathyroid Hormone
PubMed: 9576972
DOI: 10.1007/s002239900464 -
Endocrinology and Metabolism Clinics of... Sep 1989Interpretation of serum immunoreactive PTH measurements requires an understanding of the secretion, metabolism, and heterogeneity of circulating immunoreactive PTH. Both... (Review)
Review
Interpretation of serum immunoreactive PTH measurements requires an understanding of the secretion, metabolism, and heterogeneity of circulating immunoreactive PTH. Both intact hormone and biologically inactive carboxyl fragments containing the middle and C-terminal regions are secreted by the parathyroid glands. Inactive fragments also are produced peripherally by metabolism of intact hormone by liver and kidney. Inactive fragments represent 75 to 95% of the total immunoreactivity in serum, a consequence of their long half-life in vivo as compared with intact hormone. Immunoassays for PTH can be divided into those measuring intact hormone (N-terminal, intact) and those measuring both inactive fragments and intact hormone (mid-region, C-terminal, polyvalent). The latter principally measures inactive fragments because of their greater concentration as compared with intact hormone in peripheral serum. The clinical utility of PTH assays varies considerably because of differences in their specificity and sensitivity. Serum PTH levels have been more often observed to be elevated in individuals with primary hyperparathyroidism with the use of research quality radioimmunoassays that recognize both inactive fragments and intact hormone than with conventional N-terminal or intact assays. Homologous mid-region assays have provided exceptional clinical sensitivity in confirming primary hyperparathyroidism. Comparison of a sensitive mid-region radioimmunoassay with a recently developed two-site, noncompetitive chemiluminescent immunoassay for intact PTH indicated that both methods were highly useful in the differential diagnosis of hypercalcemia. The mid-region assay provided the best diagnostic sensitivity in primary hyperparathyroidism with more elevated levels of PTH. The sensitivity of the intact assay was good, a significant improvement over conventional N-terminal and intact assays. The specificity of the intact assay was clearly superior, with measured PTH levels found to be suppressed to below normal in most subjects with hypercalcemia associated with malignancy. In contrast, measured levels were primarily normal with the mid-region assay. The higher levels of immunoreactive PTH observed in nonparathyroid hypercalcemia with the mid-region assay are in agreement with the measurement of biologically inactive carboxyl fragments, which continue to be secreted in hypercalcemia.
Topics: Amino Acid Sequence; Animals; Diagnosis, Differential; Humans; Hypercalcemia; Immunoassay; Molecular Sequence Data; Parathyroid Hormone; Radioimmunoassay
PubMed: 2673765
DOI: No ID Found -
Journal of Bone and Mineral Research :... Mar 2010Parathyroid hormone (PTH) plays an essential role in regulating calcium and bone homeostasis in the adult, but whether PTH is required at all for regulating...
Parathyroid hormone (PTH) plays an essential role in regulating calcium and bone homeostasis in the adult, but whether PTH is required at all for regulating fetal-placental mineral homeostasis and skeletal development is uncertain. We hypothesized that despite its low circulating levels during fetal life, PTH plays a critical role in regulating these processes. To address this, we examined two different genetic models of PTH deficiency. Pth null mice have enlarged parathyroids that are incapable of making PTH, whereas Gcm2 null mice lack parathyroids but have PTH that arises from the thymus. Pth nulls served as a model of complete absence of PTH, whereas Gcm2 nulls were a model of severe hypoparathyroidism. We determined that PTH contributes importantly to fetal mineral homeostasis because in its absence a fetal hypoparathyroid phenotype results with hypocalcemia, hypomagnesemia, hyperphosphatemia, low amniotic fluid mineral content, and reduced skeletal mineral content. We also determined that PTH is expressed in the placenta, regulates the placental expression of genes involved in calcium and other solute transfer, and may directly stimulate placental calcium transfer. Although parathyroid hormone-related protein (PTHrP) acts in concert with PTH to regulate fetal mineral homeostasis and placental calcium transfer, unlike PTH, it does not upregulate in response to fetal hypocalcemia.
Topics: Animals; Female; Homeostasis; Mice; Mice, Knockout; Parathyroid Hormone; Placenta; Placental Circulation; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 19968565
DOI: 10.1359/jbmr.090825 -
Kidney International Mar 2009We used RNA interference, which causes sequence-specific degradation of target mRNAs to suppress the production of parathyroid hormone by cells of patients with...
We used RNA interference, which causes sequence-specific degradation of target mRNAs to suppress the production of parathyroid hormone by cells of patients with secondary hyperparathyroidism in vitro and in vivo. Transfection of small interfering RNA (siRNA) against human parathyroid hormone into monolayers of parathyroid cells cultured from these patients caused a dose-dependent decrease of secretion and mRNA levels with 80% or more suppression using 40 nM siRNA. Parathyroid cells cultured on non-adherent plastic produced spheroid cell aggregates which secreted parathyroid hormone for more than 150 days. Transfection of these spheroids with 50 nM targeted siRNA decreased parathyroid hormone production to 20% of the control level, with half of them being suppressed for 50 days. When parathyroid cells were transplanted into the livers of athymic nude mice, plasma human parathyroid hormone rose to 100-300 pg/ml within one month and remained at about this level for at least 39 days. Systemic delivery of hormone-targeted siRNA into these mice caused a dose-dependent suppression of circulating human parathyroid hormone for at least one month, with a maximum 80% suppression achieved by 80 microg of siRNA. Our study shows that hormone secretion by parathyroid cells of patients with secondary hyperparathyriodism can be suppressed both in vitro and in vivo by targeted siRNAs.
Topics: Animals; Drug Delivery Systems; Humans; Hyperparathyroidism, Secondary; Mice; Parathyroid Hormone; RNA Interference; RNA, Small Interfering
PubMed: 19037254
DOI: 10.1038/ki.2008.568 -
Current Opinion in Oncology Jan 2009To discuss recent findings and controversies regarding intraoperative parathyroid hormone monitoring (IPM) in guiding parathyroidectomy. (Review)
Review
PURPOSE OF REVIEW
To discuss recent findings and controversies regarding intraoperative parathyroid hormone monitoring (IPM) in guiding parathyroidectomy.
RECENT FINDINGS
IPM is being frequently used in guiding surgeons to complete excision of abnormal glands during parathyroidectomy for sporadic primary hyperparathyroidism (SPHPT). This adjunct is now being used in many centers around the world and has become a standard of care in the treatment of SPHPT. As the use of this technique developed, the understanding of what was necessary to return patients with hyperparathyroidism to a eucalcemic state, namely, excision of all parathyroid tissue secreting high amount of parathyroid hormone, was recognized. Two major controversies have developed during the evolution of IPM guided parathyroidectomy. One is that gland excision based on this modality may not recognize all abnormal glands, which, if not excised, will result in operative failure or recurrent hyperparathyroidism. The second disagreement is a technical one and concerns the best intraoperative protocol to be used.
SUMMARY
Parathyroidectomy for SPHPT is highly successful regardless of the operative approach used. Despite the controversies summarized in the present review, IPM has been shown to be accurate as an adjunct to guide parathyroidectomy and has changed the operative management of SPHPT.
Topics: Humans; Hyperparathyroidism, Primary; Monitoring, Intraoperative; Parathyroid Hormone; Parathyroidectomy
PubMed: 19291832
DOI: 10.1097/cco.0b013e328319ec2f -
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 -
Endocrinology Feb 2021LA-PTH is a long-acting parathyroid hormone (PTH) peptide analogue in preclinical development for hypoparathyroidism (HP). Like native PTH, LA-PTH contains a methionine...
LA-PTH is a long-acting parathyroid hormone (PTH) peptide analogue in preclinical development for hypoparathyroidism (HP). Like native PTH, LA-PTH contains a methionine at position 8 (Met8) that is predicted to be critical for function. We assessed the impact of Met oxidation on the functional properties of LA-PTH and control PTH ligands. Oxidation of PTH(1-34) resulted in marked (~20-fold) reductions in binding affinity on the PTH receptor-1 (PTHR1) in cell membranes, similarly diminished potency for 3',5'-cyclic AMP signaling in osteoblastic cell lines (SaOS-2 and UMR106), and impaired efficacy for raising blood calcium in mice. Surprisingly, oxidation of LA-PTH resulted in little or no change in these functional responses. The signaling potency of oxidized-LA-PTH was, however, reduced approximately 40-fold compared to LA-PTH in cells expressing a PTHR1 construct that lacks the N-terminal extracellular domain (ECD). Molecular modeling revealed that while Met8 of both LA-PTH and PTH(1-34) is situated within the orthosteric ligand-binding pocket of the receptor's transmembrane domain bundle (TMD), the Met8 sidechain position is shifted for the 2 ligands so that on Met8 oxidation of PTH(1-34), steric clashes occur that are not seen with oxidized LA-PTH. The findings suggest that LA-PTH and PTH(1-34) engage the receptor differently in the Met8-interaction environment of the TMD bundle, and that this interaction environment can be allosterically influenced by the ECD component of the ligand-receptor complex. The findings should be useful for the future development of novel PTH-based peptide therapeutics for diseases of bone and mineral ion metabolism.
Topics: Animals; Calcium; Cell Line, Tumor; Drug Evaluation, Preclinical; Female; HEK293 Cells; Humans; Hypoparathyroidism; Methionine; Mice; Models, Molecular; Norleucine; Oxidation-Reduction; Parathyroid Hormone; Rats; Receptor, Parathyroid Hormone, Type 1
PubMed: 33242090
DOI: 10.1210/endocr/bqaa216 -
FEBS Letters Nov 2022In acidic secretory granules of mammalian cells, peptide hormones including the parathyroid hormone are presumably stored in the form of functional amyloid fibrils....
In acidic secretory granules of mammalian cells, peptide hormones including the parathyroid hormone are presumably stored in the form of functional amyloid fibrils. Mature PTH, however, is considerably positively charged in acidic environments, a condition known to impede unassisted self-aggregation into fibrils. Here, we studied the role of the polyanion heparin on promoting fibril formation of PTH. Employing ITC, CD spectroscopy, NMR, SAXS, and fluorescence-based assays, we could demonstrate that heparin binds PTH with submicromolar affinity and facilitates its conversion into fibrillar seeds, enabling rapid formation of amyloid fibrils under acidic conditions. In the absence of heparin, PTH remained in a soluble monomeric state. We suspect that heparin-like surfaces are required in vivo to convert PTH efficiently into fibrillar deposits.
Topics: Animals; Heparin; Amyloid; Parathyroid Hormone; Scattering, Small Angle; X-Ray Diffraction; Hydrogen-Ion Concentration; Mammals
PubMed: 35903816
DOI: 10.1002/1873-3468.14455 -
Danish Medical Bulletin Feb 1996
Review
Topics: Calcium; Humans; Hyperparathyroidism; Parathyroid Hormone; Reference Values
PubMed: 8906978
DOI: No ID Found