Osteoporosis (OP) is a degenerative bone disease characterised by decreased bone mass, microstructural bone degradation, and an increased risk of fracture. The pathogenesis of OP is linked to an imbalance in bone metabolism, which includes disruptions in the bone formation and bone resorption processes, which are regulated by osteoclasts and osteoblasts, respectively. When the rate of bone formation is slower than the rate of bone resorption, OP takes hold. Bone resorption inhibitors and bone formation enhancers are two drugs used to treat OP. The most common drug class is bone resorption inhibitors, which include bisphosphonates, hormone replacement therapy (HRT), selective oestrogen receptor modulators (SERMs), calcitonin, and rank ligand inhibitors.  These treatments boost bone mineral density (BMD) by preventing bone resorption. The researchers were able to introduce several genetic mutations in the zebrafish and modify genes that also have an important impact on bone quality and result in fragile bone diseases in humans. It now appears that these “mutated” zebrafish exhibit remarkably similar features as human patients, such as fractured ribs, bowed bones and facial deformities.

Disease models are critical in drug research and development. Cell models, on the other hand, are overly simplified and cannot accurately represent overall physiology or provide much information on drug metabolism in vivo. Animal models, such as mice, have cost and time constraints, limiting their use in high-throughput screening. Zebrafish, on the other hand, have several advantages, including rapid development and small, transparent bodies. Furthermore, between zebrafish and mammals, developmental signalling pathways and related genes are highly conserved. The mechanisms of bone development in vertebrates have been conserved throughout evolution. Wnt/-catenin, TGF-, and Hedgehog signalling are all important in osteoblast development. Lower vertebrate bone formation is similar to that of mammals, with endochondral and intramembranous ossification regulated by a variety of transcription factors and hormones. Osterix, runx2a/b, col10a1, and osteonectin, which are homologous to human bone formation regulators, are key regulators involved in zebrafish bone formation. Overall, these shared developmental characteristics provide a rationale for using zebrafish as a research model for diseases of the maturing skeleton, and possibly of the adult skeleton. Transgenic technology, which uses reporter genes inserted downstream of a tissue-specific promoter to produce fluorescence in specific organs, can be used to produce fluorescence in specific organs. In zebrafish, this technology has been used to study gene function at the molecular level as well as for drug screening.

The imbalance between osteoclasts and osteoblasts is a common feature of OP. In GIOP zebrafish, gene expression analyses revealed that osterix, osteocalcin, and osteopontin were downregulated, while tracp was upregulated. This meant that osteoblast formation was suppressed while osteoclast formation was boosted. These findings support the canonical molecular mechanisms of GIOP. By increasing the expression of osteoblast-specific transcription factors, FE alleviated OP-like symptoms. Tracp, the osteoclast-related transcription factor, was unaffected. This implies that FE only has an effect on osteoblasts. It is more likely that FE promotes the growth of osteoblasts rather than inhibiting the formation of osteoclasts.

Because zebrafish have historically been used to better understand disease onset due to their fast-embryonic development properties, zebrafish ageing studies have only recently been conducted to model age-related diseases such as OA and OP. More research is needed to fully establish an OP-like phenotype in zebrafish, as it was previously determined in its teleost cousin medaka .The advantageous properties described in this review should be further exploited to aid in the development of OP drugs. Zebrafish respond appropriately to increased mechanical loading, with the cellular (transcriptional) response initiating increased bone formation and mineralization in the loaded bone elements, which are easily quantifiable. Because zebrafish and mammalian bone morphology differ (6), a pharmacological assay should concentrate on the complex tissue and osteoblast-osteoclast interactions that underpin OP pathology. Because traditional rodent and in vitro co-culture have limitations for large-scale drug discovery in a genetic context, zebrafish can serve as a primary testing platform, opening the door to work on gene specific compound discovery that has been identified as a risk factor in human genetic studies. Following primary safety testing, these identified compounds can be tested in mammalian OP models to see how they affect BMD, bone strength, and trabeculation. Exploiting these opportunities fully by using zebrafish as a primary screening model will open up exciting new avenues for performing pharmacogenetics on OP patients.