Recent advances in understanding molecular and clinical heterogeneity in osteoarthritis: one disease or several?

The failure to develop disease modifying drugs in osteoarthritis (OA) has been a frustration for academia and industry as well as a disappointment for patients. Many reasons have contributed to this failure, most notably an incomplete understanding of its pathogenesis and a lack of clarity on whether OA is one disease or a collection of several different diseases. The challenges in OA are compounded by the heterogeneous clinical presentation of disease and its slow insidious course in most individuals. Patient reported pain is variable, only partly correlates with structural disease, and is complicated by the development of central sensitisation leading to pain amplification in many, especially women. Happily, in recent years, a number of substantial advances have helped to define the core tenets of disease; revealing the breadth of the biology and its variance across patients with different clinical phenotypes. These advances have included large-scale agnostic approaches to unravel the biology through multi-omic analyses, improved clinical phenotyping, and phenotype-endotype comparisons. What emerges is evidence of one core biological pathway, suggesting a shared common disease process, with evidence of biology that changes as disease progresses and with clinical phenotypes such as biological sex, age and obesity. Together, these findings support the need for both shared therapeutic strategies and more personalised approaches in OA, which are likely to enhance future treatment success.