Tenofovir and bone : age-dependent effects in a zebrafish animal model

Background: New drugs against HIV infection are associated with important side effects, including impaired bone health. An important reduction of bone mineral density has been repeatedly described in adult but not in young patients receiving tenofovir disoproxil fumarate (TDF) as part of their antiretroviral regimen. The present study aimed to verify the presence and the characteristics of the adverse effects of TDF on skeletal tissue by using the Danio rerio (zebrafish) model. Methods: TDF administration via microinjection in the yolk has been used for embryo study. Water treatment with TDF and scale analysis by morphological, histological and biochemical experiments have been used for adult animals. Results: TDF administration via microinjection in the yolk did not induce any significant effect on mineralization rate and did not produce deformity of the skeletal structure, or growth or vitality impairment of the embryos. TDF exposure in adult zebrafish induced an age-related reduction of the osteoblastic activity marker alkaline phosphatase (up to -44%) and an increase of the osteoclastic activity marker tartrateresistant acid phosphatase (up to +57%) in the scales. Old fish treated with TDF exhibited an osteoporotic-like phenotype with resorption area along the edge of the scale. Conclusions: This study demonstrated that in zebrafish, as in humans, TDF shows a catabolic bone effect related to age and underlined the ultimate utility of using teleost fish as a model to assess the effects of drugs on bone tissue.