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Alendronate induces skeletal alterations in the chicken embryonic development model
Wladimir Gushiken de Campos1, Rita Araújo2, Celso Augusto Lemos Júnior3
1Department of Stomatology, School of Dentistry, University of Sao Paulo, São Paulo, Brazil.
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.
Insights
Alendronate negatively impacts embryonic bone development in a dose-dependent manner. This bisphosphonate drug reduces bone formation and mineralization, potentially posing risks during pregnancy.
Area of Science:
- Pharmacology
- Developmental Biology
- Orthopedics
Background:
- Alendronate, a nitrogen-containing bisphosphonate, is widely used for osteoporosis but its effects on osteoblasts and embryonic development are less understood.
- Alendronate can cross the placental barrier, raising concerns for pregnant women of reproductive age undergoing alendronate therapy.
- Understanding alendronate's impact on embryonic bone development is crucial given its potential teratogenic effects.
Purpose of the Study:
- To investigate the dose-dependent effects of alendronate on embryonic skeletal development.
- To assess alendronate's influence on osteogenic and osteoclastogenic gene expression and inflammatory activation in developing bone.
- To evaluate the safety of alendronate during embryonic development using a translational animal model.
Main Methods:
- Utilized a chicken embryo model, exposing embryos to varying alendronate concentrations (1.5E-10M to 1.5E-7M) from day 7 of osteogenesis for 4 days.
- Conducted histomorphometric analysis with histochemical staining and microtomographic analysis to assess skeletal development and mineralization.
- Performed gene expression analysis for osteoclastogenic, osteogenic, and inflammatory markers.
Main Results:
- Alendronate exposure demonstrated a dose-dependent inhibition of skeletal growth and mineralization, with a significant reduction in bone volume and surface at 1.5E-7M.
- Decreased expression of osteoclastogenic/osteoclastic genes and osteoblastogenic/osteogenic genes (30-50% reduction at 1.5E-7M) indicated impaired bone formation.
- Evidence of increased inflammatory activation was observed, potentially contributing to the observed negative effects on bone development.
Conclusions:
- Alendronate exerts a dose-dependent negative influence on embryonic bone development.
- The findings highlight potential risks associated with alendronate exposure during critical periods of embryonic skeletal formation.
- Further research is warranted to fully elucidate the mechanisms and clinical implications of alendronate's effects on embryonic development.
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