Does standalone/combined subchondral bone marrow-derived mesenchymal stem/stromal cell injection offer significantly better clinical benefit to intraarticular injection in knee osteoarthritis?

BACKGROUND Knee osteoarthritis (OA) is a degenerative joint disease traditionally viewed through the lens of cartilage degradation. However, emerging evidence positions subchondral bone pathology - particularly bone marrow lesions (BMLs) - as a key contributor to pain, progression, and structural deterioration. Mesenchymal stem cell exhaustion within the osteoarthritic subchondral zone further impairs intrinsic repair mechanisms, reinforcing the rationale for biologic interventions. AIM To evaluate the clinical efficacy of bone marrow aspirate concentrate (BMAC) therapy for knee OA, comparing subchondral vs intra-articular delivery routes, and elucidating the therapeutic impact on symptom relief and structural preservation. METHODS Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, five clinical studies were included - comprising three randomized controlled trials and two prospective cohorts - with pooled data from 298 knees. Data on functional outcomes, imaging findings, and progression to total knee arthroplasty (TKA) were extracted and qualitatively synthesized. RESULTS Subchondral BMAC injections demonstrated superior improvements compared to intra-articular injection or placebo: Knee Injury and Osteoarthritis Outcome Score improved from 49.1 ± 1.9 to 61.2 ± 6.3 at 12 months (P < 0.05), Knee Society Score increased from 57 ± 12 to 87.3 ± 12 at two years, and Western Ontario and McMaster Universities Arthritis Index scores showed significant improvement favoring combined approaches. Magnetic resonance imaging analyses revealed mean BML volume regression of 2.1 cm3, with 80% of knees avoiding TKA over 13-year follow-up. Magnetic resonance imaging analyses revealed regression of BMLs and increased cartilage preservation in subchondral-treated knees. Long-term data indicated delayed progression to TKA and biomechanical improvements (e.g. , Hip-Knee-Ankle angle correction). No major adverse events were reported. CONCLUSION Targeting subchondral bone with BMAC addresses underlying OA pathology and may offer disease-modifying potential beyond symptom relief. These findings support a paradigm shift toward whole-joint biologic therapy, positioning the subchondral matrix as a therapeutic epicenter in OA management.