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Sex-Specific Differences in G_sα-Mediated Signaling Downstream of PTH1R Activation by Abaloparatide in Bone.

ABSTRACT: Teriparatide, recombinant parathyroid hormone (PTH[1-34]), and abaloparatide, an analogue of PTH related-peptide (PTHrP[1-34]), are both anabolic medications for osteoporosis that target the PTH receptor PTH1R. PTH1R is a G protein-coupled receptor, and the stimulatory Gs protein is an important mediator of the anabolic actions of PTH1R activation in bone. We have published that mice lacking the α subunit of Gs in osteoprogenitors do not increase bone mass in response to PTH(1-34). Unexpectedly, however, PTH(1-34) still increases osteoblast numbers and bone formation rate in male mice, suggesting that PTH1R may have both Gs-dependent and -independent actions in bone. Here we examine the role of Gs signaling in the anabolic actions of abaloparatide. We find that abaloparatide increases bone formation in male mice with postnatal deletion of G_sα in Osx-expressing osteoprogenitors (P-G_sα^OsxKO mice) but not in female P-G_sα^OsxKO mice. Therefore, abaloparatide has anabolic effects on bone in male but not female mice that appear to be independent of Gs-mediated signaling. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

SUBMITTER: Swami S

PROVIDER: S-EPMC9751656 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Sex-Specific Differences in G<sub>s</sub>α-Mediated Signaling Downstream of PTH1R Activation by Abaloparatide in Bone.

Swami Srilatha S Johnson Joshua J Vecchi Lawrence A LA Kim Matthew J MJ Lanske Beate B Johnson Rachelle W RW Wu Joy Y JY

JBMR plus 20221124 12

Teriparatide, recombinant parathyroid hormone (PTH[1-34]), and abaloparatide, an analogue of PTH related-peptide (PTHrP[1-34]), are both anabolic medications for osteoporosis that target the PTH receptor PTH1R. PTH1R is a G protein-coupled receptor, and the stimulatory Gs protein is an important mediator of the anabolic actions of PTH1R activation in bone. We have published that mice lacking the α subunit of Gs in osteoprogenitors do not increase bone mass in response to PTH(1-34). Unexpectedly, ...[more]

PMID: 36530190

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Project description:Background and objectiveAbaloparatide, an anabolic osteoporosis treatment administered by subcutaneous (SC) injection, increases bone mineral density (BMD) and reduces fracture risk in postmenopausal women with osteoporosis. The abaloparatide-solid Microstructured Transdermal System [abaloparatide-sMTS (Kindeva, St Paul, MN, USA)], which delivers abaloparatide intradermally, is in development to provide an alternative method for abaloparatide delivery. The objective of this study was to evaluate the ability of subjects to self-administer abaloparatide-sMTS, based on pharmacokinetic and pharmacodynamic markers.MethodsIn this single-arm, open-label, Phase 1b study, 22 healthy postmenopausal women aged 50-85 years with low BMD were trained to self-administer abaloparatide-sMTS 300 μg once daily to the thigh for 5 min for 29 days. The primary endpoint was systemic exposure to abaloparatide. Secondary endpoints included percent change from baseline in serum procollagen type I N-terminal propeptide (s-PINP), patient experience, and safety.ResultsAll 22 subjects completed the study. At baseline, mean age was 65.2 years, mean total hip T-score was - 1.32, and mean lumbar spine T-score was - 1.98. On Day 1, the median time to reach maximum concentration (Tmax) for abaloparatide-sMTS was 0.33 h and geometric mean (CV %) maximum concentration (Cmax) and area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC0-t) were 447 (38.0) pg/mL and 678 (45.3) pg·h/mL, respectively; the pharmacokinetic profile was similar on Days 15 and 29. Median percentage change in s-PINP was 45.4% and 64.4% at Days 15 and 29, respectively. The most common adverse events (AEs) were application site erythema, pain, and swelling, which were mostly of mild or moderate severity. No AEs led to study drug withdrawal and no serious AEs were reported. The success rate for self-administration at first application was 99.7%, and subject acceptability was high (~ 4.5 on a 5-point Likert Scale).ConclusionsSubjects successfully self-administered abaloparatide-sMTS, which provided a consistent pharmacokinetic profile over 29 days and produced s-PINP increases from baseline similar to that observed in the pivotal trial with abaloparatide-SC. Observed patient experience along with the clinical data support continued clinical development of abaloparatide-sMTS.Trial registration numberNCT04366726, Date of registration 04/29/2020, retrospectively registered.

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Sex-Specific Differences in G_sα-Mediated Signaling Downstream of PTH1R Activation by Abaloparatide in Bone.

Publications

Sex-Specific Differences in G<sub>s</sub>α-Mediated Signaling Downstream of PTH1R Activation by Abaloparatide in Bone.

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Dataset Information

Sex-Specific Differences in Gsα-Mediated Signaling Downstream of PTH1R Activation by Abaloparatide in Bone.

Publications

Sex-Specific Differences in G<sub>s</sub>α-Mediated Signaling Downstream of PTH1R Activation by Abaloparatide in Bone.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Sex-Specific Differences in G_sα-Mediated Signaling Downstream of PTH1R Activation by Abaloparatide in Bone.