Effect of alendronate on survival and bone properties in Nothobranchius furzeri: insights from a model of accelerated aging.

Alendronate effectively inhibits osteoclastic bone resorption and is considered as first line treatment of osteoporosis. Additionally, several studies suggest a beneficial effect on mortality that goes beyond life-extending effects attributed to the well-established fracture risk reduction. However, mechanisms of the mortality reducing effect of bisphosphonates are unclear. The turquoise killifish Nothobranchius furzeri (N. furzeri), a well-known model of accelerated aging, exhibits an extremely short life cycle and thus could represent a suitable model for survival studies. The aim of this study was to test the effect of alendronate on the life span and bone properties of N. furzeri. At the age of 16 weeks 89 female fish were divided into a treatment (10 μM alendronate, n = 44) and a control (n = 45) group and monitored for survival. Vertebral bodies of deceased fish were examined by micro-CT and bone histomorphometry. RNA sequencing and gene expression analysis was done from isolated tissues of heart, spleen, liver, muscle and kidney. The alendronate group showed a higher survival (+7%; p = 0.0070). Micro-CT evaluation showed higher values for bone (+2%; p = 0.0013) and tissue mineral density (+3%; p = 0.0159) in the control group. Bone histomorphometry displayed higher values for number of osteoblasts/bone perimeter (p = 0.0340) in the alendronate group. RNA sequencing revealed differences in gene expression and biological function under alendronate treatment. Furthermore, we determined a reduced ZNF703 expression in the alendronate group. Our results indicate that alendronate has a positive effect on survival of N. furzeri and alters bone mineralization. Moreover, it effects several non-bone related pathways and leads to strong organ-specific effects.