Osteoporosis predisposes patients to spinal fragility fractures. Imaging plays a key role in the diagnosis and prognostication of these osteoporotic vertebral fractures (OVF). However, the current imaging knowledge base for OVF is lacking sufficient standardisation to enable effective risk prognostication. OVF have been shown to be more prevalent in Caucasian patient cohorts in comparison to the Eastern Asian population. These population-based differences in risk for developing OVF suggest that there could be genetic and epigenetic factors that drive the pathogenesis of osteoporosis, low bone mineral density (BMD) and OVF. Several genetic loci have been associated with a higher vertebral fracture risk, although at varying degrees of significance. The present challenge is clarifying whether these associations are specific to vertebral fractures or osteoporosis more generally. Furthermore, these factors could be exploited for diagnostic interpretation as biomarkers [including novel long non-coding (lnc)RNAs, micro (mi)RNAs and circular (circ)RNAs]. The extent of methylation of genes, alongside post-translational histone modifications, have shown to affect several interlinked pathways that converge on the regulation of bone deposition and resorption, partially through their influence on osteoblast and osteoclast differentiation. Lastly, in addition to biomarkers, several exciting new imaging modalities could add to the established dual-energy X-ray absorptiometry (DXA) method used for BMD assessment. New technologies, and novel sequences within existing imaging modalities, may be able to quantify the quality of bone in addition to the BMD and bone structure; these are making progress through various stages of development from the pre-clinical sphere through to deployment in the clinical setting. In this mini review, we explore the literature to clarify the genetic and epigenetic factors associated with spinal fragility fractures and delineate the causal genes, pathways and interactions which could drive different risk profiles. We also outline the cutting-edge imaging modalities which could transform diagnostic protocols for OVF.