Discontinuation of PTH therapy amplifies bone loss by increasing oxidative stress: An event ameliorated by sequential IL-17 neutralizing antibody therapy

Osteoporosis leads to excessive bone resorption which is not accompanied by equal amount of bone formation. PTH (1−34) forms the mainstay of bone anabolic therapy. Intermittent PTH (iPTH) has the ability to reconstruct skeleton, a property not shared by other anti-resorptives. In initial phases of P...

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Autores principales:	Krishna Bhan Singh, Reena Rai, Sonu Khanka, Divya Singh
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	Postmenopausal osteoporosis Bone mineral density PTH Bone formation Cortical bone Bone strength Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/4fd26d8fb43d4d9ab0581fffa0b40601
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spelling	oai:doaj.org-article:4fd26d8fb43d4d9ab0581fffa0b406012021-11-28T04:28:06ZDiscontinuation of PTH therapy amplifies bone loss by increasing oxidative stress: An event ameliorated by sequential IL-17 neutralizing antibody therapy0753-332210.1016/j.biopha.2021.112390https://doaj.org/article/4fd26d8fb43d4d9ab0581fffa0b406012022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0753332221011768https://doaj.org/toc/0753-3322Osteoporosis leads to excessive bone resorption which is not accompanied by equal amount of bone formation. PTH (1−34) forms the mainstay of bone anabolic therapy. Intermittent PTH (iPTH) has the ability to reconstruct skeleton, a property not shared by other anti-resorptives. In initial phases of PTH treatment, bone formation exceeds bone resorption. However, gradually this phase is replaced by increased bone resorption. Thus, a replacement post PTH discontinuation is much needed. Studies with bisphosphonates and Denosumab post PTH withdrawal have yielded promising but variable results. Thus, there is scope for trying new combinations. Our previous studies have shown the superior skeletal effects of neutralizing IL17 antibody (NIL17) over anti-RANKL antibody. Thus, here we investigated if sequential treatment of NIL17 after PTH withdrawal (SHIFT) could serve as a promising therapeutic approach for osteoporosis treatment. Our results show that PTH withdrawal (PTH-W) led to mitigation of its anabolic effects as evidenced by reduced BMD, bone trabecular and cortical microarchitectural parameters. In the continuous PTH (PTH-C) and the Shift group, all these parameters were preserved as par with the sham group. Shift therapy also significantly increased PINP levels. Most importantly, serum CTX-I levels and osteoclast numbers, which were elevated in PTH groups were significantly suppressed in NIL17 monotherapy and shift group. Also, expression of FOXO1 and ATF-4, the main regulators of redox balance and function in osteoblasts, were found to be enhanced maximally in the sequential therapy group. Our study thus advocates use of NIL17 as a replacement therapeutic option post PTH discontinuation.Krishna Bhan SinghReena RaiSonu KhankaDivya SinghElsevierarticlePostmenopausal osteoporosisBone mineral densityPTHBone formationCortical boneBone strengthTherapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 145, Iss , Pp 112390- (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	Postmenopausal osteoporosis Bone mineral density PTH Bone formation Cortical bone Bone strength Therapeutics. Pharmacology RM1-950
spellingShingle	Postmenopausal osteoporosis Bone mineral density PTH Bone formation Cortical bone Bone strength Therapeutics. Pharmacology RM1-950 Krishna Bhan Singh Reena Rai Sonu Khanka Divya Singh Discontinuation of PTH therapy amplifies bone loss by increasing oxidative stress: An event ameliorated by sequential IL-17 neutralizing antibody therapy
description	Osteoporosis leads to excessive bone resorption which is not accompanied by equal amount of bone formation. PTH (1−34) forms the mainstay of bone anabolic therapy. Intermittent PTH (iPTH) has the ability to reconstruct skeleton, a property not shared by other anti-resorptives. In initial phases of PTH treatment, bone formation exceeds bone resorption. However, gradually this phase is replaced by increased bone resorption. Thus, a replacement post PTH discontinuation is much needed. Studies with bisphosphonates and Denosumab post PTH withdrawal have yielded promising but variable results. Thus, there is scope for trying new combinations. Our previous studies have shown the superior skeletal effects of neutralizing IL17 antibody (NIL17) over anti-RANKL antibody. Thus, here we investigated if sequential treatment of NIL17 after PTH withdrawal (SHIFT) could serve as a promising therapeutic approach for osteoporosis treatment. Our results show that PTH withdrawal (PTH-W) led to mitigation of its anabolic effects as evidenced by reduced BMD, bone trabecular and cortical microarchitectural parameters. In the continuous PTH (PTH-C) and the Shift group, all these parameters were preserved as par with the sham group. Shift therapy also significantly increased PINP levels. Most importantly, serum CTX-I levels and osteoclast numbers, which were elevated in PTH groups were significantly suppressed in NIL17 monotherapy and shift group. Also, expression of FOXO1 and ATF-4, the main regulators of redox balance and function in osteoblasts, were found to be enhanced maximally in the sequential therapy group. Our study thus advocates use of NIL17 as a replacement therapeutic option post PTH discontinuation.
format	article
author	Krishna Bhan Singh Reena Rai Sonu Khanka Divya Singh
author_facet	Krishna Bhan Singh Reena Rai Sonu Khanka Divya Singh
author_sort	Krishna Bhan Singh
title	Discontinuation of PTH therapy amplifies bone loss by increasing oxidative stress: An event ameliorated by sequential IL-17 neutralizing antibody therapy
title_short	Discontinuation of PTH therapy amplifies bone loss by increasing oxidative stress: An event ameliorated by sequential IL-17 neutralizing antibody therapy
title_full	Discontinuation of PTH therapy amplifies bone loss by increasing oxidative stress: An event ameliorated by sequential IL-17 neutralizing antibody therapy
title_fullStr	Discontinuation of PTH therapy amplifies bone loss by increasing oxidative stress: An event ameliorated by sequential IL-17 neutralizing antibody therapy
title_full_unstemmed	Discontinuation of PTH therapy amplifies bone loss by increasing oxidative stress: An event ameliorated by sequential IL-17 neutralizing antibody therapy
title_sort	discontinuation of pth therapy amplifies bone loss by increasing oxidative stress: an event ameliorated by sequential il-17 neutralizing antibody therapy
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/4fd26d8fb43d4d9ab0581fffa0b40601
work_keys_str_mv	AT krishnabhansingh discontinuationofpththerapyamplifiesbonelossbyincreasingoxidativestressaneventamelioratedbysequentialil17neutralizingantibodytherapy AT reenarai discontinuationofpththerapyamplifiesbonelossbyincreasingoxidativestressaneventamelioratedbysequentialil17neutralizingantibodytherapy AT sonukhanka discontinuationofpththerapyamplifiesbonelossbyincreasingoxidativestressaneventamelioratedbysequentialil17neutralizingantibodytherapy AT divyasingh discontinuationofpththerapyamplifiesbonelossbyincreasingoxidativestressaneventamelioratedbysequentialil17neutralizingantibodytherapy
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Discontinuation of PTH therapy amplifies bone loss by increasing oxidative stress: An event ameliorated by sequential IL-17 neutralizing antibody therapy

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