Knee Osteoarthritis, Hormonal Decline, and Chronic Inflammation in Midlife Women: Hormone Therapy as a Modulator of the Osteoarthritis Disease Environment: An Orthopaedic and Integrative Clinical Perspective

Background: Knee osteoarthritis (OA) is traditionally framed as a mechanical “wear-and-tear” disorder. Contemporary evidence supports OA as a whole-joint, immunometabolic and neurosensory disease in which low-grade inflammation modulates tissue homeostasis and pain. In midlife women, the menopause transition coincides with abrupt endocrine changes that plausibly amplify inflammatory tone, alter neuromuscular function, and increase pain sensitisation—often with symptoms disproportionate to imaging. Objective: To synthesise the biological rationale and clinical evidence linking menopausal hormonal decline with OA-relevant inflammatory and neuromuscular mechanisms, and to propose a collaborative orthopaedic model integrating menopause health expertise. Methods: Narrative synthesis of mechanistic, epidemiologic, and clinical trial data on OA inflammation, menopause-related musculoskeletal symptoms, and hormone therapy effects on pain/function and musculoskeletal resilience. Evidence is interpreted with attention to outcome type (symptoms vs structural progression), confounding in observational studies, and timing/continuity considerations. Key Findings: (1) OA pain and disability correlate imperfectly with radiographic severity, consistent with synovitis, adipose-derived mediators, subchondral remodelling, and peripheral/central sensitisation. (2) Perimenopause is associated with increased prevalence of musculoskeletal pain, suggesting a biological inflection period rather than linear age-related decline. (3) Oestrogen decline plausibly shifts immune signalling toward pro-inflammatory pathways (e.g., IL-6/TNF-α/NF-κB), while progesterone and androgen changes may influence sleep quality, recovery capacity, muscle strength, and neuromuscular control—factors strongly linked to knee OA outcomes. (4) Menopausal hormone therapy (when appropriately indicated and supervised) may reduce joint pain in some women and may improve musculoskeletal resilience; however, evidence for disease-modifying structural effects on OA remains limited and confounded. Clinical Implications: Orthopaedic care for midlife women with knee OA should include endocrine-aware phenotyping, screening for menopause-transition symptom clusters, and structured referral pathways to women’s hormonal health specialists. Optimising the systemic biological environment may enhance the durability of rehabilitation, regenerative strategies, and surgical outcomes. Conclusion: Menopause transition biology is a clinically relevant modifier of OA symptom expression and functional decline. Integrating hormonal health expertise into orthopaedic pathways is not scope expansion—it is precision care aligned with modern OA biology.