Subchondral Bone–Cartilage Unit Interactions in Osteoarthritis: Mechanisms, Clinical Implications, and Emerging Therapeutic Strategies

Abstract

Osteoarthritis (OA) is a multifaceted, degenerative joint disorder characterized by the progressive destruction of articular cartilage and alterations in subchondral bone architecture. Growing evidence highlights the crucial interplay between the subchondral bone and cartilage as a driving force in OA pathogenesis. This review examines the epidemiology, pathophysiological mechanisms, clinical features, diagnostic approaches, and recent advances in the understanding and management of the subchondral bone–cartilage unit in OA. Emphasis is placed on translational research and clinical guidelines relevant to healthcare professionals managing OA patients.

Introduction

Osteoarthritis is the most prevalent form of arthritis, leading to pain, disability, and diminished quality of life among aging populations worldwide. Once considered a disease of cartilage alone, OA is now recognized as a disorder of the entire joint, with the subchondral bone–cartilage unit playing a pivotal role in disease initiation and progression. The functional and structural crosstalk between cartilage and subchondral bone is mediated through biochemical signals and mechanical forces, influencing joint homeostasis and pathogenic cascades. Understanding these interactions is essential for the development of mechanism-based diagnostic and therapeutic strategies.

Epidemiology / Disease Burden

OA affects over 300 million individuals globally, with prevalence rates increasing alongside aging demographics and rising obesity rates. The knee, hip, and hand joints are most commonly involved. OA is a significant cause of morbidity, accounting for substantial healthcare utilization and economic burden. Subchondral bone changes, such as sclerosis, cyst formation, and bone marrow lesions, are observed in up to 80% of radiographically confirmed OA cases and are associated with symptomatic progression, highlighting the need for deeper insight into the subchondral bone–cartilage interface.

Pathophysiology

The subchondral bone–cartilage unit comprises the articular cartilage, calcified cartilage, subchondral bone plate, and subchondral trabecular bone. In OA, disruption of this unit occurs through abnormal mechanical loading, microdamage, and altered bone remodeling. Early OA features increased bone turnover, microcracks, and bone marrow lesions, with subsequent sclerosis and formation of osteophytes. Biochemical crosstalk between chondrocytes and osteoblasts mediated by cytokines, growth factors, and small molecules promotes catabolic processes, angiogenesis, and neurogenesis, contributing to pain and structural deterioration. Recent studies implicate the Wnt/β-catenin, TGF-β, and RANK/RANKL/OPG pathways in mediating these interactions. Mechanistically, subchondral bone changes can precede cartilage degeneration, suggesting a bidirectional pathogenic relationship and therapeutic target potential.

Risk Factors

Major OA risk factors include advanced age, female sex, obesity, prior joint injury, genetic predisposition, and abnormal joint loading. Metabolic factors, such as diabetes and dyslipidemia, are increasingly implicated in OA pathogenesis. These risk factors contribute to altered biomechanical forces and metabolic derangements at the subchondral bone–cartilage unit, accelerating disease progression. Notably, bone mineral density and turnover markers may reflect disease activity and risk of progression, providing potential biomarkers for risk stratification and monitoring.

Clinical Features

OA presents with joint pain, stiffness, crepitus, and progressive loss of function. Subchondral bone pathology contributes to pain via bone marrow lesions, increased intraosseous pressure, and the ingrowth of nociceptive nerve fibers. Clinical examination may reveal joint line tenderness, bony enlargement, and restricted range of motion. Advanced disease features deformity and instability. Recognizing the contribution of subchondral bone alterations to clinical symptoms is important for comprehensive assessment and targeted interventions.

Diagnosis

The diagnosis of OA is based on clinical evaluation supported by imaging. Conventional radiographs reveal joint space narrowing, osteophyte formation, subchondral sclerosis, and cysts. Magnetic resonance imaging (MRI) is more sensitive for detecting early changes, including cartilage defects, bone marrow lesions, and subchondral cysts, providing valuable insights into the integrity of the subchondral bone–cartilage unit. Emerging imaging modalities, such as quantitative MRI and novel biomarkers, are under investigation for early detection and monitoring.

Treatment & Management

OA management is multimodal, including patient education, weight reduction, physical therapy, and pharmacological interventions aimed at symptom control. Nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular corticosteroids are commonly used for pain relief. Surgical interventions, such as osteotomy and joint replacement, are reserved for advanced disease. Modifying the subchondral bone–cartilage unit through bisphosphonates, bone-targeted agents, or regenerative approaches is under active investigation. Optimizing biomechanical alignment and joint loading remains a cornerstone of management, given the interplay between mechanical stress and joint degeneration.

Recent Advances / Emerging Therapies

Recent research has focused on disease-modifying OA drugs (DMOADs) targeting bone remodeling and cartilage preservation. Selective inhibition of catabolic cytokines, Wnt pathway modulators, and TGF-β antagonists are being evaluated in clinical trials. Subchondral bone-targeted therapies, such as bisphosphonates, strontium ranelate, and anti-nerve growth factor antibodies, show potential to alleviate pain and slow structural progression. Regenerative approaches, including stem cell therapies and tissue engineering, aim to restore the integrity of the subchondral bone–cartilage unit. Molecular imaging and advanced biomarkers are enabling earlier diagnosis and personalized therapeutic strategies.

Guideline Recommendations

Current guidelines from leading rheumatology and orthopedic societies emphasize a holistic, patient-centered approach integrating symptom management with joint preservation strategies. Early identification of subchondral bone alterations is recommended using advanced imaging in selected cases. Non-pharmacological interventions remain foundational, with judicious use of pharmacological and surgical options based on disease severity. Emerging evidence supports the potential role of subchondral bone–targeted therapies, though further high-quality studies are warranted before routine adoption.

Conclusion

The subchondral bone–cartilage unit is central to the pathogenesis and progression of osteoarthritis, offering novel opportunities for early diagnosis and targeted therapy. Advances in molecular and imaging technologies are refining our understanding of joint biology and enabling mechanism-based interventions. Clinicians should remain abreast of evolving evidence to optimize care for OA patients, integrating established guidelines with emerging strategies that address the subchondral bone–cartilage interplay.