Bisphosphonate effects on Nothobranchius furzeri

Alendronate, which belongs to the group of nitrogen containing bisphosphonates (aminobisphosphonates), is known to effectively inhibit osteoclastic bone resorption and is used in the treatment of osteoporosis. Previous observational studies have found a beneficial effect of nitrogen containing bisphosphonates on mortality; nevertheless, the mechanisms of mortality reduction by this type of bisphosphonates are largely unexplored. At the present moment, only one randomized controlled clinical trial, that has observed mortality as a secondary endpoint, exists. Due to this, the mortality lowering effect need to be investigated in more detail. To facilitate this, the turquoise killifish, Nothobranchius furzeri, was selected for this study. Nothobranchius furzeri is an established model of accelerated aging that has an extremely short life cycle (3-7 months) and therefore is ideally suited as a model for our study. In order to be able to study the effect of alendronate on mortality in Nothobranchius furzeri, 100 16-week-old female fish will be treated with alendronate and monitored for survival. In addition, further 100 untreated control fish will be observed. After the death of the fish, bones from both fish groups (treated and untreated) will be examined by micro-CT analyses, histology and histomorphometry. Furthermore, immunohistochemistry, RNA-sequencing and PCR analysis will be performed. This study can be used to determine how alendronate treatment affects the lifespan of Nothobranchius furzeri. We expect that treatment with alendronate will increase survival. Additionally, the effects of alendronate on bone remodeling, the immune system, and the cardiovascular system will be investigated. The generated results of this study will serve as a basis for investigating the mechanisms contributing to the possible mortality-lowering effects of nitrogen containing bisphosphonates. In addition, with this study, we aim to establish Nothobranchius furzeri as a future model for the study of bisphosphonate-mediated effects and research of future osteoporosis therapies.