Alendronate induces skeletal alterations in the chicken embryonic development model

Wladimir Gushiken de Campos; Rita Araújo; Celso Augusto Lemos Júnior; Pedro de Sousa Gomes

doi:10.1016/j.taap.2023.116673

Alendronate induces skeletal alterations in the chicken embryonic development model

Toxicol Appl Pharmacol. 2023 Oct 1:476:116673. doi: 10.1016/j.taap.2023.116673. Epub 2023 Aug 29.

Authors

Wladimir Gushiken de Campos¹, Rita Araújo², Celso Augusto Lemos Júnior³, Pedro de Sousa Gomes⁴

Affiliations

¹ Department of Stomatology, School of Dentistry, University of Sao Paulo, São Paulo, Brazil.
² Department of Stomatology, School of Dentistry, University of Sao Paulo, São Paulo, Brazil; Laboratory for Bone Metabolism and Regeneration, Faculty of Dental Medicine, University of Porto, 4200-393 Porto, Portugal.
³ Department of Oral Medicine, Faculdade de Odontologia, Universidade de São Paulo, São Paulo, Brazil.. Electronic address: calemosj@usp.br.
⁴ Laboratory for Bone Metabolism and Regeneration, Faculty of Dental Medicine, University of Porto, 4200-393 Porto, Portugal. Electronic address: pgomes@fmd.up.pt.

PMID: 37652309
DOI: 10.1016/j.taap.2023.116673

Abstract

Alendronate, a nitrogen-containing bisphosphonate, has reported long-term clinical success in the management of distinct bone-related conditions, particularly in the modulation of post-menopausal osteoporosis. Nonetheless, whether the inhibitory activity over osteoclastic cells' functionality is widely acknowledged, contradictory evidence arises from the assessment of alendronate activity over osteoblastic populations. This may be of particular relevance in situations in which bone formation exceeds bone resorption, with further emphasis on embryonic development, since alendronate can cross the placental barrier and alendronate-based therapies are being extended into women of reproductive age. Accordingly, the present study aims to assess the effects of alendronate, at distinct concentrations (1.5E^-10M to 1.5E^-7M) on bone tissue development, within a translational animal model - the embryonic chicken development model. Embryos, at the beginning of osteogenesis (day 7) were exposed to different alendronate concentrations for 4 days. Embryos were following characterized for skeletal development by histomorphometric analysis upon histochemical staining, microtomographic analysis, and gene expression assessment of genes related to osteoclastogenic/osteoclastic and osteoblastogenic/osteogenic differentiation, as well as to the immuno-inflammatory activation. The findings revealed that exposure to alendronate had a dose-dependent impact on skeletal growth and mineralization. This effect was evidenced by diminished bone volume and reduced bone surface parameters, with the 1.5E^-7M concentration leading to a remarkable reduction of over 50%. Additionally, a decreased osteoclastogenic/osteoclastic gene expression was verified, associated with a diminished osteoblastogenic/osteogenic program - within the 30-50% range for 1.5E-7 M, supporting the diminished bone formation process. An increased inflammatory activation may contribute, at least in part, to the attained outcomes. Overall present findings suggest a negative influence of alendronate on the embryonic bone development process in a dose-dependent manner, highlighting the potential risk of alendronate use during embryonic development.

Keywords: Alendronate; Animal model; Bisphosphonates; Bone Development.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alendronate* / toxicity
Animals
Chick Embryo
Chickens
Embryonic Development
Female
Osteogenesis*
Placenta
Pregnancy

Substances

Alendronate