Assessment of Strategies for Safe Drug Discontinuation and Transition of Denosumab Treatment in PMO—Insights From a Mechanistic PK/PD Model of Bone Turnover

Denosumab (Dmab) treatment against postmenopausal osteoporosis (PMO) has proven very efficient in increasing bone mineral density (BMD) and reducing the risk of bone fractures. However, concerns have been recently raised regarding safety when drug treatment is discontinued. Mechanistic pharmacokinet...

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Autores: Martínez Reina, Francisco Javier, Calvo Gallego, José Luis, Martin, Madge, Pivonka, Peter
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2022
País:España
Recursos:Universidad de Sevilla (US)
Repositório:idUS. Depósito de Investigación de la Universidad de Sevilla
OAI Identifier:oai:idus.us.es:11441/138370
Acesso em linha:https://hdl.handle.net/11441/138370
https://doi.org/10.3389/fbioe.2022.886579
Access Level:Acceso aberto
Palavra-chave:Postmenopausal osteoporosis
Bone remodelling
Bone mineralisation
Denosumab discontinuation
RANK-RANKL-OPG pathway
PK-PD modelling
Osteoclast precursors
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spelling Assessment of Strategies for Safe Drug Discontinuation and Transition of Denosumab Treatment in PMO—Insights From a Mechanistic PK/PD Model of Bone TurnoverMartínez Reina, Francisco JavierCalvo Gallego, José LuisMartin, MadgePivonka, PeterPostmenopausal osteoporosisBone remodellingBone mineralisationDenosumab discontinuationRANK-RANKL-OPG pathwayPK-PD modellingOsteoclast precursorsDenosumab (Dmab) treatment against postmenopausal osteoporosis (PMO) has proven very efficient in increasing bone mineral density (BMD) and reducing the risk of bone fractures. However, concerns have been recently raised regarding safety when drug treatment is discontinued. Mechanistic pharmacokinetic-pharmacodynamic (PK-PD) models are the most sophisticated tools to develop patient specific drug treatments of PMO to restore bone mass. However, only a few PK-PD models have addressed the effect of Dmab drug holidays on changes in BMD. We showed that using a standard bone cell population model (BCPM) of bone remodelling it is not possible to account for the spike in osteoclast numbers observed after Dmab discontinuation. We show that inclusion of a variable osteoclast precursor pool in BCPMs is essential to predict the experimentally observed rapid rise in osteoclast numbers and the associated increases in bone resorption. This new model also showed that Dmab withdrawal leads to a rapid increase of damage in the bone matrix, which in turn decreases the local safety factor for fatigue failure. Our simulation results show that changes in BMD strongly depend on Dmab concentration in the central compartment. Consequently, bone weight (BW) might play an important factor in calculating effective Dmab doses. The currently clinically prescribed constant Dmab dose of 60 mg injected every 6 months is less effective in increasing BMD for patients with high BW (2.5% for 80 kg in contrast to 8% for 60 kg after 6 years of treatment). However, bone loss observed 24 months after Dmab withdrawal is less pronounced in patients with high BW (3.5% for 80kg and 8.5% for 60 kg). Finally, we studied how to safely discontinue Dmab treatment by exploring several transitional and combined drug treatment strategies. Our simulation results indicate that using transitional reduced Dmab doses are not effective in reducing rapid bone loss. However, we identify that use of a bisphosphonate (BP) is highly effective in avoiding rapid bone loss and increase in bone tissue damage compared to abrupt withdrawal of Dmab. Furthermore, the final values of BMD and damage were not sensitive to the time of administration of the BP.Frontiers Media S.A.Ingeniería Mecánica y FabricaciónTEP111: Ingeniería mecánicaFEDERJunta de Andalucía - Consejería de Economía, Conocimiento, Empresas y UniversidadUniversidad de Sevilla2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/138370https://doi.org/10.3389/fbioe.2022.886579reponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésFrontiers in Bioengineering and Biotechnology, 10, 886579.P18-RT-3611https://www.frontiersin.org/articles/10.3389/fbioe.2022.886579/fullinfo:eu-repo/semantics/openAccessoai:idus.us.es:11441/1383702026-06-17T12:51:07Z
dc.title.none.fl_str_mv Assessment of Strategies for Safe Drug Discontinuation and Transition of Denosumab Treatment in PMO—Insights From a Mechanistic PK/PD Model of Bone Turnover
title Assessment of Strategies for Safe Drug Discontinuation and Transition of Denosumab Treatment in PMO—Insights From a Mechanistic PK/PD Model of Bone Turnover
spellingShingle Assessment of Strategies for Safe Drug Discontinuation and Transition of Denosumab Treatment in PMO—Insights From a Mechanistic PK/PD Model of Bone Turnover
Martínez Reina, Francisco Javier
Postmenopausal osteoporosis
Bone remodelling
Bone mineralisation
Denosumab discontinuation
RANK-RANKL-OPG pathway
PK-PD modelling
Osteoclast precursors
title_short Assessment of Strategies for Safe Drug Discontinuation and Transition of Denosumab Treatment in PMO—Insights From a Mechanistic PK/PD Model of Bone Turnover
title_full Assessment of Strategies for Safe Drug Discontinuation and Transition of Denosumab Treatment in PMO—Insights From a Mechanistic PK/PD Model of Bone Turnover
title_fullStr Assessment of Strategies for Safe Drug Discontinuation and Transition of Denosumab Treatment in PMO—Insights From a Mechanistic PK/PD Model of Bone Turnover
title_full_unstemmed Assessment of Strategies for Safe Drug Discontinuation and Transition of Denosumab Treatment in PMO—Insights From a Mechanistic PK/PD Model of Bone Turnover
title_sort Assessment of Strategies for Safe Drug Discontinuation and Transition of Denosumab Treatment in PMO—Insights From a Mechanistic PK/PD Model of Bone Turnover
dc.creator.none.fl_str_mv Martínez Reina, Francisco Javier
Calvo Gallego, José Luis
Martin, Madge
Pivonka, Peter
author Martínez Reina, Francisco Javier
author_facet Martínez Reina, Francisco Javier
Calvo Gallego, José Luis
Martin, Madge
Pivonka, Peter
author_role author
author2 Calvo Gallego, José Luis
Martin, Madge
Pivonka, Peter
author2_role author
author
author
dc.contributor.none.fl_str_mv Ingeniería Mecánica y Fabricación
TEP111: Ingeniería mecánica
FEDER
Junta de Andalucía - Consejería de Economía, Conocimiento, Empresas y Universidad
Universidad de Sevilla
dc.subject.none.fl_str_mv Postmenopausal osteoporosis
Bone remodelling
Bone mineralisation
Denosumab discontinuation
RANK-RANKL-OPG pathway
PK-PD modelling
Osteoclast precursors
topic Postmenopausal osteoporosis
Bone remodelling
Bone mineralisation
Denosumab discontinuation
RANK-RANKL-OPG pathway
PK-PD modelling
Osteoclast precursors
description Denosumab (Dmab) treatment against postmenopausal osteoporosis (PMO) has proven very efficient in increasing bone mineral density (BMD) and reducing the risk of bone fractures. However, concerns have been recently raised regarding safety when drug treatment is discontinued. Mechanistic pharmacokinetic-pharmacodynamic (PK-PD) models are the most sophisticated tools to develop patient specific drug treatments of PMO to restore bone mass. However, only a few PK-PD models have addressed the effect of Dmab drug holidays on changes in BMD. We showed that using a standard bone cell population model (BCPM) of bone remodelling it is not possible to account for the spike in osteoclast numbers observed after Dmab discontinuation. We show that inclusion of a variable osteoclast precursor pool in BCPMs is essential to predict the experimentally observed rapid rise in osteoclast numbers and the associated increases in bone resorption. This new model also showed that Dmab withdrawal leads to a rapid increase of damage in the bone matrix, which in turn decreases the local safety factor for fatigue failure. Our simulation results show that changes in BMD strongly depend on Dmab concentration in the central compartment. Consequently, bone weight (BW) might play an important factor in calculating effective Dmab doses. The currently clinically prescribed constant Dmab dose of 60 mg injected every 6 months is less effective in increasing BMD for patients with high BW (2.5% for 80 kg in contrast to 8% for 60 kg after 6 years of treatment). However, bone loss observed 24 months after Dmab withdrawal is less pronounced in patients with high BW (3.5% for 80kg and 8.5% for 60 kg). Finally, we studied how to safely discontinue Dmab treatment by exploring several transitional and combined drug treatment strategies. Our simulation results indicate that using transitional reduced Dmab doses are not effective in reducing rapid bone loss. However, we identify that use of a bisphosphonate (BP) is highly effective in avoiding rapid bone loss and increase in bone tissue damage compared to abrupt withdrawal of Dmab. Furthermore, the final values of BMD and damage were not sensitive to the time of administration of the BP.
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/11441/138370
https://doi.org/10.3389/fbioe.2022.886579
url https://hdl.handle.net/11441/138370
https://doi.org/10.3389/fbioe.2022.886579
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Frontiers in Bioengineering and Biotechnology, 10, 886579.
P18-RT-3611
https://www.frontiersin.org/articles/10.3389/fbioe.2022.886579/full
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Frontiers Media S.A.
publisher.none.fl_str_mv Frontiers Media S.A.
dc.source.none.fl_str_mv reponame:idUS. Depósito de Investigación de la Universidad de Sevilla
instname:Universidad de Sevilla (US)
instname_str Universidad de Sevilla (US)
reponame_str idUS. Depósito de Investigación de la Universidad de Sevilla
collection idUS. Depósito de Investigación de la Universidad de Sevilla
repository.name.fl_str_mv
repository.mail.fl_str_mv
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