Bisphosphonates impair the onset of bone formation at remodeling sites

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Bisphosphonates impair the onset of bone formation at remodeling sites. / Jensen, Pia Rosgaard; Andersen, Thomas Levin; Chavassieux, Pascale; Roux, Jean Paul; Delaisse, Jean Marie.

I: Bone, Bind 145, 115850, 04.2021.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

Harvard

Jensen, PR, Andersen, TL, Chavassieux, P, Roux, JP & Delaisse, JM 2021, 'Bisphosphonates impair the onset of bone formation at remodeling sites', Bone, bind 145, 115850. https://doi.org/10.1016/j.bone.2021.115850

APA

Jensen, P. R., Andersen, T. L., Chavassieux, P., Roux, J. P., & Delaisse, J. M. (2021). Bisphosphonates impair the onset of bone formation at remodeling sites. Bone, 145, [115850]. https://doi.org/10.1016/j.bone.2021.115850

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Jensen, Pia Rosgaard ; Andersen, Thomas Levin ; Chavassieux, Pascale ; Roux, Jean Paul ; Delaisse, Jean Marie. / Bisphosphonates impair the onset of bone formation at remodeling sites. I: Bone. 2021 ; Bind 145.

Bibtex

@article{a8e4a3c6fa084722a9f72c9cbdb63836,
title = "Bisphosphonates impair the onset of bone formation at remodeling sites",
abstract = "Bisphosphonates are widely used anti-osteoporotic drugs targeting osteoclasts. They strongly inhibit bone resorption, but also strongly reduce bone formation. This reduced formation is commonly ascribed to the mechanism maintaining the resorption/formation balance during remodeling. The present study provides evidence for an additional mechanism where bisphosphonates actually impair the onset of bone formation after resorption. The evidence is based on morphometric parameters recently developed to assess the activities reversing resorption to formation. Herein, we compare these parameters in cancellous bone of alendronate- and placebo-treated postmenopausal osteoporotic patients. Alendronate increases the prevalence of eroded surfaces characterized by reversal cells/osteoprogenitors at low cell density and remote from active bone surfaces. This indicates deficient cell expansion on eroded surfaces – an event that is indispensable to start formation. Furthermore, alendronate decreases the coverage of these eroded surfaces by remodeling compartment canopies, a putative source of reversal cells/osteoprogenitors. Finally, alendronate strongly decreases the activation frequency of bone formation, and decreases more the formative compared to the eroded surfaces. All these parameters correlate with each other. These observations lead to a model where bisphosphonates hamper the osteoprogenitor recruitment required to initiate bone formation. This effect results in a larger eroded surface, thereby explaining the well-known paradox that bisphosphonates strongly inhibit bone resorption without strongly decreasing eroded surfaces. The possible mechanism for hampered osteoprogenitor recruitment is discussed: bisphosphonates may decrease the release of osteogenic factors by the osteoclasts, and/or bisphosphonates released by osteoclasts may act directly on neighboring osteoprogenitor cells as reported in preclinical studies.",
keywords = "Anti-resorptives, Bone remodeling, Human bone histomorphometry, Osteoblasts, Osteoporosis",
author = "Jensen, {Pia Rosgaard} and Andersen, {Thomas Levin} and Pascale Chavassieux and Roux, {Jean Paul} and Delaisse, {Jean Marie}",
year = "2021",
month = apr,
doi = "10.1016/j.bone.2021.115850",
language = "English",
volume = "145",
journal = "Bone",
issn = "8756-3282",
publisher = "Elsevier Inc.",

}

RIS

TY - JOUR

T1 - Bisphosphonates impair the onset of bone formation at remodeling sites

AU - Jensen, Pia Rosgaard

AU - Andersen, Thomas Levin

AU - Chavassieux, Pascale

AU - Roux, Jean Paul

AU - Delaisse, Jean Marie

PY - 2021/4

Y1 - 2021/4

N2 - Bisphosphonates are widely used anti-osteoporotic drugs targeting osteoclasts. They strongly inhibit bone resorption, but also strongly reduce bone formation. This reduced formation is commonly ascribed to the mechanism maintaining the resorption/formation balance during remodeling. The present study provides evidence for an additional mechanism where bisphosphonates actually impair the onset of bone formation after resorption. The evidence is based on morphometric parameters recently developed to assess the activities reversing resorption to formation. Herein, we compare these parameters in cancellous bone of alendronate- and placebo-treated postmenopausal osteoporotic patients. Alendronate increases the prevalence of eroded surfaces characterized by reversal cells/osteoprogenitors at low cell density and remote from active bone surfaces. This indicates deficient cell expansion on eroded surfaces – an event that is indispensable to start formation. Furthermore, alendronate decreases the coverage of these eroded surfaces by remodeling compartment canopies, a putative source of reversal cells/osteoprogenitors. Finally, alendronate strongly decreases the activation frequency of bone formation, and decreases more the formative compared to the eroded surfaces. All these parameters correlate with each other. These observations lead to a model where bisphosphonates hamper the osteoprogenitor recruitment required to initiate bone formation. This effect results in a larger eroded surface, thereby explaining the well-known paradox that bisphosphonates strongly inhibit bone resorption without strongly decreasing eroded surfaces. The possible mechanism for hampered osteoprogenitor recruitment is discussed: bisphosphonates may decrease the release of osteogenic factors by the osteoclasts, and/or bisphosphonates released by osteoclasts may act directly on neighboring osteoprogenitor cells as reported in preclinical studies.

AB - Bisphosphonates are widely used anti-osteoporotic drugs targeting osteoclasts. They strongly inhibit bone resorption, but also strongly reduce bone formation. This reduced formation is commonly ascribed to the mechanism maintaining the resorption/formation balance during remodeling. The present study provides evidence for an additional mechanism where bisphosphonates actually impair the onset of bone formation after resorption. The evidence is based on morphometric parameters recently developed to assess the activities reversing resorption to formation. Herein, we compare these parameters in cancellous bone of alendronate- and placebo-treated postmenopausal osteoporotic patients. Alendronate increases the prevalence of eroded surfaces characterized by reversal cells/osteoprogenitors at low cell density and remote from active bone surfaces. This indicates deficient cell expansion on eroded surfaces – an event that is indispensable to start formation. Furthermore, alendronate decreases the coverage of these eroded surfaces by remodeling compartment canopies, a putative source of reversal cells/osteoprogenitors. Finally, alendronate strongly decreases the activation frequency of bone formation, and decreases more the formative compared to the eroded surfaces. All these parameters correlate with each other. These observations lead to a model where bisphosphonates hamper the osteoprogenitor recruitment required to initiate bone formation. This effect results in a larger eroded surface, thereby explaining the well-known paradox that bisphosphonates strongly inhibit bone resorption without strongly decreasing eroded surfaces. The possible mechanism for hampered osteoprogenitor recruitment is discussed: bisphosphonates may decrease the release of osteogenic factors by the osteoclasts, and/or bisphosphonates released by osteoclasts may act directly on neighboring osteoprogenitor cells as reported in preclinical studies.

KW - Anti-resorptives

KW - Bone remodeling

KW - Human bone histomorphometry

KW - Osteoblasts

KW - Osteoporosis

UR - http://www.scopus.com/inward/record.url?scp=85099858479&partnerID=8YFLogxK

U2 - 10.1016/j.bone.2021.115850

DO - 10.1016/j.bone.2021.115850

M3 - Journal article

C2 - 33465485

AN - SCOPUS:85099858479

VL - 145

JO - Bone

JF - Bone

SN - 8756-3282

M1 - 115850

ER -