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OR13-05 Longitudinal Changes In Bone Turnover Following Withdrawal Of RANKL Inhibition
Disclosure: A.S. Kim: None. A. Castro-Martinez: None. V. Taylor: None. J. Center: None. C.M. Girgis: None. P.I. Croucher: None. M.M. Mcdonald: None. Denosumab is an effective osteoporosis treatment, preventing bone loss by inhibiting RANKL. However, stopping denosumab leads to rebound bone mineral d...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10555373/ http://dx.doi.org/10.1210/jendso/bvad114.472 |
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author | Kim, Albert S Castro-Martinez, Ariel Taylor, Victoria Center, Jacqueline Girgis, Christian M Croucher, Peter I Mcdonald, Michelle M |
author_facet | Kim, Albert S Castro-Martinez, Ariel Taylor, Victoria Center, Jacqueline Girgis, Christian M Croucher, Peter I Mcdonald, Michelle M |
author_sort | Kim, Albert S |
collection | PubMed |
description | Disclosure: A.S. Kim: None. A. Castro-Martinez: None. V. Taylor: None. J. Center: None. C.M. Girgis: None. P.I. Croucher: None. M.M. Mcdonald: None. Denosumab is an effective osteoporosis treatment, preventing bone loss by inhibiting RANKL. However, stopping denosumab leads to rebound bone mineral density(BMD) loss. This is due to accelerated bone resorption by osteoclasts. Serum bone turnover markers such as P1NP and CTX have been utilised in clinical practice to guide sequential therapy following denosumab discontinuation. However, an optimal strategy has not been established. Understanding the temporal changes in osteoclast activity will guide safe, effective sequential therapy following denosumab discontinuation. We hypothesised that serum TRAP5b, a marker of enzymatic activity of osteoclasts, would be a more useful marker in this context to guide sequential treatment following denosumab discontinuation. Seven-week-old female C57BL/6 mice were treated with 2-weeks of thrice-weekly OPG:Fc(10mg/kg) to inhibit RANKL then withdrawn from therapy (OPG-W) or saline(vehicle). Longitudinal BMD and serum TRAP5b were measured throughout the study. Mice were harvested at weeks 2, 8, 11 and 13 to allow a large volume of serum to be collected to concurrently measure serum TRAP5b and the products of collagen formation and breakdown, serum P1NP and CTX respectively . Following OPG:Fc withdrawal, BMD peaked at week 8 in OPG-W mice (92.94 vs75.09mg/cm(2), p<0.0001), started to decline at week 10 and normalised to vehicle levels by week 13. Longitudinally, serum TRAP was suppressed by week 2 (0.05 vs 11.90U/L, p<0.0001) and remained suppressed until week 8, following which serum TRAP levels rose progressively to 64% above vehicle levels at week 12 (17.86 vs 10.92U/L, p<0.0001). The rise in TRAP between weeks 8 to 10 preceded the decline in BMD.Serum TRAP was significantly elevated in OPG-W mice at week 11 (15.45 vs 11.46U/L, p=0.01) whereas serum P1NP and CTX remained equivalent to vehicle levels. Serum TRAP, P1NP and CTX were significantly higher in OPG-W mice at week 13 by which time BMD had reached vehicle levels. Our findings show that rebound decline in BMD has already occurred by the time bone turnover markers used in clinical practice (P1NP and CTX) rise above vehicle levels. A significant overshoot in serum TRAP occurs earlier and prior to bone loss and may better inform sequential therapy following denosumab discontinuation. Presentation: Friday, June 16, 2023 |
format | Online Article Text |
id | pubmed-10555373 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-105553732023-10-06 OR13-05 Longitudinal Changes In Bone Turnover Following Withdrawal Of RANKL Inhibition Kim, Albert S Castro-Martinez, Ariel Taylor, Victoria Center, Jacqueline Girgis, Christian M Croucher, Peter I Mcdonald, Michelle M J Endocr Soc Bone And Mineral Metabolism Disclosure: A.S. Kim: None. A. Castro-Martinez: None. V. Taylor: None. J. Center: None. C.M. Girgis: None. P.I. Croucher: None. M.M. Mcdonald: None. Denosumab is an effective osteoporosis treatment, preventing bone loss by inhibiting RANKL. However, stopping denosumab leads to rebound bone mineral density(BMD) loss. This is due to accelerated bone resorption by osteoclasts. Serum bone turnover markers such as P1NP and CTX have been utilised in clinical practice to guide sequential therapy following denosumab discontinuation. However, an optimal strategy has not been established. Understanding the temporal changes in osteoclast activity will guide safe, effective sequential therapy following denosumab discontinuation. We hypothesised that serum TRAP5b, a marker of enzymatic activity of osteoclasts, would be a more useful marker in this context to guide sequential treatment following denosumab discontinuation. Seven-week-old female C57BL/6 mice were treated with 2-weeks of thrice-weekly OPG:Fc(10mg/kg) to inhibit RANKL then withdrawn from therapy (OPG-W) or saline(vehicle). Longitudinal BMD and serum TRAP5b were measured throughout the study. Mice were harvested at weeks 2, 8, 11 and 13 to allow a large volume of serum to be collected to concurrently measure serum TRAP5b and the products of collagen formation and breakdown, serum P1NP and CTX respectively . Following OPG:Fc withdrawal, BMD peaked at week 8 in OPG-W mice (92.94 vs75.09mg/cm(2), p<0.0001), started to decline at week 10 and normalised to vehicle levels by week 13. Longitudinally, serum TRAP was suppressed by week 2 (0.05 vs 11.90U/L, p<0.0001) and remained suppressed until week 8, following which serum TRAP levels rose progressively to 64% above vehicle levels at week 12 (17.86 vs 10.92U/L, p<0.0001). The rise in TRAP between weeks 8 to 10 preceded the decline in BMD.Serum TRAP was significantly elevated in OPG-W mice at week 11 (15.45 vs 11.46U/L, p=0.01) whereas serum P1NP and CTX remained equivalent to vehicle levels. Serum TRAP, P1NP and CTX were significantly higher in OPG-W mice at week 13 by which time BMD had reached vehicle levels. Our findings show that rebound decline in BMD has already occurred by the time bone turnover markers used in clinical practice (P1NP and CTX) rise above vehicle levels. A significant overshoot in serum TRAP occurs earlier and prior to bone loss and may better inform sequential therapy following denosumab discontinuation. Presentation: Friday, June 16, 2023 Oxford University Press 2023-10-05 /pmc/articles/PMC10555373/ http://dx.doi.org/10.1210/jendso/bvad114.472 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Bone And Mineral Metabolism Kim, Albert S Castro-Martinez, Ariel Taylor, Victoria Center, Jacqueline Girgis, Christian M Croucher, Peter I Mcdonald, Michelle M OR13-05 Longitudinal Changes In Bone Turnover Following Withdrawal Of RANKL Inhibition |
title | OR13-05 Longitudinal Changes In Bone Turnover Following Withdrawal Of RANKL Inhibition |
title_full | OR13-05 Longitudinal Changes In Bone Turnover Following Withdrawal Of RANKL Inhibition |
title_fullStr | OR13-05 Longitudinal Changes In Bone Turnover Following Withdrawal Of RANKL Inhibition |
title_full_unstemmed | OR13-05 Longitudinal Changes In Bone Turnover Following Withdrawal Of RANKL Inhibition |
title_short | OR13-05 Longitudinal Changes In Bone Turnover Following Withdrawal Of RANKL Inhibition |
title_sort | or13-05 longitudinal changes in bone turnover following withdrawal of rankl inhibition |
topic | Bone And Mineral Metabolism |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10555373/ http://dx.doi.org/10.1210/jendso/bvad114.472 |
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