Introduction

Osteoarthritis (OA) results from imbalance of proinflammatory cytokines (IL‑1α, IL‑1β, TNF‑α) disrupting cartilage metabolism and homeostasis, causing cartilage degradation. Increased interferon γ worsens inflammation and proteoglycan loss. Mild OA is managed conservatively; severe OA needs surgery. Orthobiologics and MSCs offer both symptom‑ and disease‑modifying effects.

Aim

To evaluate the efficacy and safety of allogeneic, pooled, bone marrow-derived mesenchymal stromal cells (BMMSCs) for treating Grade 2 and 3 knee osteoarthritis (OA) in a double-blind, randomized, placebo-controlled phase 3 study. 

Patient Profile

• Adults aged 40–65 years, male or female, with BMI <30 kg/m², symptomatic primary knee osteoarthritis requiring analgesics for ≥6 weeks. 
• Radiographic KL grade 2–3 OA with knee pain causing functional difficulty. 
• Participants consented, avoided other stem cell therapies for 2 years.

Methods

Study Design

• Phase 3 study was designed as a randomized, double blind, multicentre, placebo – controlled study.
• Conducted across 15 hospitals in India from January 2019 to July 2022 
• 146 patients were randomized into two groups.
  • BMMSCs treatment (73 patients) and placebo (73 patients)
• BMMSC group received intra-articular injections of25 million cells in 2 ml suspension followed by 20 mg hyaluronic acid (HA).
• Placebo group received 2 ml placebo followed by HA. 
• Patients were followed for 24 months, with assessments at 1 week, 1, 3, 6, 12, 18, and 24 months.

Primary and Secondary Endpoints

• Primary Endpoint :Change in WOMAC Composite Index at 12 months. 
• Secondary Endpoint: WOMAC sub-scores (pain, stiffness, physical function), VAS scores, MRI assessments (T2 mapping and cartilage volume), and biomarkers (urinary CTX-II and serum IL-10).

Results

Clinical Outcomes

Figure 1: Mean values of the WOMAC score over time.

                   

*P<0.0001

Figure 2: Percentage reduction in the WOMAC total score over time

  

Figure 3: Percentage reduction in WOMAC Sub‑Scores with BMMSCs

^*P < 0.0001

Table 1 : Percentage change of WOMAC  pain score, stiffness, physical function over time 

	1 mo	3 mo	6 mo	12 mo	18 mo	24 mo
WOMAC Pain
Placebo	-17.50	-22.90	-8.70	0.90	-0.40	11.60
BMMSCs	-16.50	-25.60	-35.60	-45.40	-54.80	-61.50
WOMAC (Stiffness)
Placebo	-16.10	21.70	-3.70	15.50	17.30	20.90
BMMSCs	-17.00	-28.40	-35.60	-39.80	-46.10	-56.30
WOMAC (Physical function)
Placebo	-19.20	-24.30	12.00	1.40	0.00	10.30
BMMSCs	-15.60	-24.90	-34.60	-44.10	-51.90	-61.20
VAS
Placebo	-23.20	26.40	-19.40	-5.40	-6.50	0.80
BMMSCs	-20.00	-26.80	-37.00	-46.80	-54.90	-63.20

 

Figure 4: Percentage of patients showing improvements in WOMAC composite score at 2 years

• VAS scores showed consistent improvement in the BMMSCs group at 12 and 24 months.
• VAS score (mm) showed significant improvements in cell arm as compared to placebo at month 12 (mean difference:41.33, P<0.0001; percentage difference: 41.33 % ) and at 24 months follow up (mean difference: 64.04; P< 0.0001; percentage difference: 64.04 %).

Table 2: Percentage change of VAS score over time 

	1 mo	3 mo	6 mo	12 mo	18 mo	24 mo
VAS
Placebo	-23.20	26.40	-19.40	-5.40	-6.50	0.80
BMMScs	-20.00	-26.80	-37.00	-46.80	-54.90	-63.20
Percentage Reduction	-	-	17.62 %	41.33 %	48.45 %	64.04%

 

MRI Outcomes

• T2 mapping showed no worsening of cartilage in the BMMSCs group, while the placebo group showed gradual worsening.
• Cartilage volume increased in the BMMSCs group, indicating chondro-protection.
• In the BMMSCs group, mean T2 relaxation times in the medial femorotibial cartilage remained within the normal range (≤39 ms) from baseline (38.1 ± 6.57 ms) to12 months (38.8 ± 6.93 ms) &24 months (36.3 ± 5.16 ms).
• In the placebo group, medial femorotibial T2 relaxation time remained above normal and showed progressive worsening over time, with significant increases from baseline to 12 and 24 months (p < 0.0001).
• Change from baseline at 24 months showcased a decrease of 1.1 ± 6.13 ms in T2 relaxation time in the BMMSCs group compared with an increase of 1.0 ± 4.42 ms in the placebo group.
• Cartilage volume in the femorotibial compartment increased in the BMMSCs group by 34.07 mm³ at 12 months and 49.81 mm³ at 24 months compared with placebo.

Figure 6: MRI T2 mapping depicting mean cartilage scores of the medial femorotibial compartment (femoral condyle) in the cell and placebo groups

Biomarkers

• At day 90 and 730, urinary CTX-II levels decreased significantly in the BMMSCs group, indicating reduced cartilage degradation. 
• Serum IL-10 levels increased in the BMMSCs group, suggesting reduced inflammation and pain. 

Safety

• BMMSCs therapy was safe, with mild, self-limiting injection site reactions reported in 4.1% of patients.
• No serious adverse events were related to the study drug.
• Fewer patients in the BMMSCs group underwent total knee replacement (TKR) compared to the placebo group (1 vs. 4).

Conclusion

• Allogeneic BMMSC therapy is safe and effective for treating Grade 2 and 3 knee OA. 
• It provides sustained relief from pain and stiffness, improves physical function, prevents cartilage degradation, and increases cartilage volume for at least 24 months, indicating chondroprotection and chondropreservation.
• The intervention is simple, non-surgical, and has the potential to preserve & protect the cartilage.

Reference 

Osteoarthr Cartil Open. 2025 Dec 11;8(1):100723