What causes osteoarthritis?

Causes of Osteoarthritis

Osteoarthritis is caused by a multifactorial combination of constitutional factors (aging, genetics, sex, obesity) and local mechanical factors (trauma, occupational stress, joint malalignment), leading to progressive cartilage loss, subchondral bone changes, and synovial inflammation. 1

Constitutional (Systemic) Risk Factors

Age

• Aging is the single most important constitutional risk factor for OA development 1
• Prevalence increases dramatically after age 65, affecting approximately 60% of men and 70% of women 2
• Age-related changes in gut microbiota contribute to systemic inflammation ("inflammaging") that may accelerate joint degeneration 1

Genetics

• OA has a significant hereditary component, with heritability estimates of 0.39-0.65 from twin studies 1
• Genetic predisposition operates independently of environmental or demographic factors 1

Sex and Hormonal Factors

• Women have higher OA incidence after age 40, particularly post-menopause 3
• Estrogen deficiency unmasks OA symptoms by enhancing pain sensitivity and inducing loss of intestinal barrier function, leading to endotoxemia and increased inflammatory markers 1, 3
• Sex hormones play a significant role in OA development, with menopausal status recognized as an independent risk factor 3

Obesity and Metabolic Factors

• Obesity increases OA risk in both weight-bearing joints (knees, hips) and non-weight-bearing joints (hands), indicating a systemic metabolic mechanism beyond mechanical loading 1
• Obesity-related metabolic inflammation involves adipokines, pro-inflammatory cytokines, abnormal metabolites, and acute phase proteins that directly damage cartilage 4
• Obesity-induced gut microbiota dysbiosis drives inflammatory processes in OA pathogenesis 1
• Metabolic syndrome components (insulin resistance, dyslipidemia, systemic inflammation) contribute to joint degeneration 1, 5

Local Mechanical Risk Factors

Trauma and Joint Injury

• Joint trauma accounts for a significant fraction of OA cases (posttraumatic OA) 1
• Risk of posttraumatic OA ranges from 20% to more than 50% even after optimal surgical management 6
• Mechanical damage triggers changes in gene expression and cartilage metabolism, initiating a cascade of cartilage degradation 6

Occupational and Recreational Stress

• Heavy physical activity and repetitive occupational joint loading are established risk factors 1
• Biomechanical stress patterns contribute to focal cartilage damage and subsequent OA development 1

Joint Malalignment

• Abnormal joint alignment alters load distribution across articular surfaces 1
• In knee OA, approximately 70-80% of joint load passes through the medial compartment during gait, accelerating compartment-specific degeneration 7

Muscle Weakness and Proprioception Deficits

• Quadriceps weakness is both a risk factor for and consequence of knee OA, creating a vicious cycle of joint instability 7
• Diminished joint position sense (proprioception) contributes to OA development and progression 7

Pathophysiological Mechanisms

Multi-Tissue Involvement

• OA involves not only cartilage but also synovial membrane, subchondral bone, ligaments, and other joint tissues from early in the disease process 1, 8
• Progressive cartilage loss leads to bone remodeling, osteophyte formation, and synovial inflammation 7, 8

Inflammatory Component

• Low-grade systemic inflammation contributes to cartilage matrix impairment and subchondral bone remodeling 4
• Metabolic-triggered inflammation from nutrient overload creates a toxic internal environment that exacerbates OA 4

Clinical Phenotypes

Based on predominant underlying pathways, four clinical phenotypes exist 5:

• Biomechanical phenotype: Driven primarily by mechanical factors and malalignment
• Osteoporotic phenotype: Associated with bone density changes
• Metabolic phenotype: Linked to obesity and metabolic syndrome
• Inflammatory phenotype: Characterized by systemic inflammation

Common Pitfalls

• Failing to recognize that OA affects multiple joint tissues, not just cartilage 8
• Overlooking hormonal factors when evaluating OA risk in women, particularly around menopause 3
• Not addressing modifiable risk factors such as obesity, muscle weakness, and biomechanical abnormalities early in the disease course 3, 9
• Assuming mechanical loading alone explains obesity-related OA, when metabolic inflammation plays a crucial independent role 1, 4