Estrogen deficiency as a common driver and integrative mechanism in osteoporosis‑osteoarthritis comorbidity (Review)

Osteoporosis and osteoarthritis have been increasingly recognized as interrelated disorders rather than isolated diseases. They often coexist in postmenopausal women, imposing a notable burden on mobility and quality of life. Estrogen deficiency, a key characteristic of menopause, represents an important, unifying risk factor that accelerates systemic bone loss while exacerbating osteochondral degeneration. Prior research has predominantly addressed osteoporosis and osteoarthritis in parallel; however, the present review offers a distinct, integrative perspective that implicates estrogen deficiency as a driver of bone‑joint unit dysfunction and highlights the mechanistic convergence of estrogen deficiency across shared pathological hubs. Specifically, the present review synthesized existing evidence demonstrating the mechanisms by which estrogen deficiency reshapes bone remodeling and cartilage metabolism; estrogen deficiency predominantly facilitates the progression of osteoporosis and osteoarthritis by amplifying common upstream drivers of these conditions, such as chronic inflammation, immune dysregulation, oxidative stress and impaired tissue repair. Furthermore, the present review integrated major signaling networks that influence this comorbidity, including the Wnt/β‑catenin, receptor activator of NF‑κB/receptor activator of NF‑κB ligand/osteoprotegerin, phosphoinositide 3‑kinase/protein kinase B and mitogen‑activated protein kinase pathways. Additionally, the present review discussed how these pathways present opportunities for biomarker development and pathway‑based intervention strategies. Notably, the present review extended this mechanistic framework to clinical translation by summarizing the diagnostic challenges encountered when evaluating patients with comorbid osteoporosis and osteoarthritis and proposing an integrated approach for risk stratification and personalized management. Overall, the present review provides a comprehensive and translational framework for estrogen deficiency‑related osteoporosis‑osteoarthritis comorbidity and underscores future directions for precision therapeutics targeting this increasingly prevalent comorbid condition.