Osteoarthritis (OA) is a chronic joint disease characterized by cartilage degradation, inflammation, and pain. While multiple factors contribute to OA development, age and sex are primary risk factors, particularly affecting postmenopausal women. The dramatic increase in OA risk after menopause suggests estrogen deficiency accelerates disease progression. This review explores the molecular mechanisms connecting aging and estrogen deficiency in OA development, focusing on key genes and pathways identified through RNA sequencing.