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Although ligands such as abaloparatide, teriparatide (hPTH 1\u201034 [TPTD]), and long\u2010acting PTH (LA\u2010PTH) show distinct biologic effects with respect to skeletal and mineral metabolism endpoints, the mechanistic basis for these clinically\u2010important differences remains incompletely understood. Previous work has revealed that differential signaling kinetics and receptor conformation engagement between different PTH1R peptide ligands. However, whether such acute membrane proximal differences translate into differences in downstream signaling output remains to be determined. Here, we directly compared short\u2010term effects of hPTH (1\u201034), abaloparatide, and LA\u2010PTH in multiple cell\u2010based PTH1R signaling assays. At the time points and ligand concentrations utilized, no significant differences were observed between these three ligands at the level of receptor internalization, \u03b2\u2010arrestin recruitment, intracellular calcium stimulation, and cAMP generation. However, abaloparatide showed significantly quicker PTH1R recycling in washout studies. Downstream of PTH1R\u2010stimulated cAMP generation, protein kinase A regulates gene expression via effects on salt inducible kinases (SIKs) and their substrates. Consistent with no differences between these ligands on cAMP generation, we observed that hPTH (1\u201034), abaloparatide, and LA\u2010PTH showed comparable effects on SIK2 phosphorylation, SIK substrate dephosphorylation, and downstream gene expression changes. Taken together, these results indicate that these PTH1R peptide agonists engage downstream intracellular signaling pathways to a comparable degree. It is possible that differences observed in vivo in preclinical and clinical models may be related to pharmacokinetic factors. It is also possible that our current in vitro systems are insufficient to perfectly match the complexities of PTH1R signaling in bona fide target cells in bone in vivo. \u00a9 2020 American Society for Bone and Mineral Research \u00a9 2020 The Authors.\n                    <jats:italic>JBMR Plus<\/jats:italic>\n                    published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.\n                  <\/jats:p>","DOI":"10.1002\/jbm4.10441","type":"journal-article","created":{"date-parts":[[2020,11,24]],"date-time":"2020-11-24T23:01:18Z","timestamp":1606258878000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Comparable Initial Engagement of Intracellular Signaling Pathways by Parathyroid Hormone Receptor Ligands Teriparatide, Abaloparatide, and Long\u2010Acting PTH"],"prefix":"10.1093","volume":"5","author":[{"given":"Tadatoshi","family":"Sato","sequence":"first","affiliation":[{"name":"Endocrine Unit, Department of Medicine Massachusetts General Hospital, Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiv","family":"Verma","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Medicine Massachusetts General Hospital, Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashok","family":"Khatri","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Medicine Massachusetts General Hospital, Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Dean","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Medicine Massachusetts General Hospital, Harvard Medical School  Boston MA 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