The role of genetic and epigenetic factors in determining the risk of spinal fragility fractures: new insights in the management of spinal osteoporosis

Abstract

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.

Significant Reduction in Bone Density as Measured by Hounsfield Units in Patients with Ankylosing Spondylitis or Diffuse Idiopathic Skeletal Hyperostosis

“…Additionally, there is a growing body of literature suggesting that the conventional DXA cutoffs, i.e., t -score > −1.0 for normal bone density, t -score −1.0 to −2.5 for osteopenia/low bone density, and t -score < −2.5 for osteoporosis, may apply differently to different racial backgrounds. Specifically, some groups have suggested that these conventional DXA cutoffs apply well to Caucasian/white populations, but may apply more poorly to patient of Asian races or other racial backgrounds [ 50 , 51 , 52 ]. Our study only included patients from a single, multi-site institution, which may limit the generalizability of the findings to other practices.…”

Evaluating Osteoporosis in Chronic Kidney Disease: Both Bone Quantity and Quality Matter

“…There is a case to be made that populations in specific Asian countries or regions may exhibit distinct risk profiles compared to Caucasian populations. Consequently, diagnostic cut-offs and models for fracture prevalence should be more appropriately tailored to these populations [14].…”

“…Classical factors associated with osteoporosis that are shared with the general population, including age, lifestyle, nutrition, physical function, genetic, epigenetic, and hormone-dependent factors, should also be considered when assessing bone fragility in a patient with CKD [14]. The coexistence of traditional and non-traditional factors specific to CKD (uremia, acidosis, inflammation, primary kidney disease, etc.)…”

The Heterogeneity of Post-Menopausal Disease Risk: Could the Basis for Why Only Subsets of Females Are Affected Be Due to a Reversible Epigenetic Modification System Associated with Puberty, Menstrual Cycles, Pregnancy and Lactation, and, Ultimately, Menopause?

“…Other factors that may also contribute to OP risk and progression include periostin levels associated with endocrine disease [32], the gut microbiota [33,34], anti-Mullerian hormone [35,36], and genetic factors [37], reviewed in [38,39], and mediators such as irisin [40]. Vascular dysfunctions such as varicose veins have also been implicated in the development of OP [41].…”