What is the evidence for mesenchymal stem cell intervention for pain reduction and functional improvement in patients with knee osteoarthritis?
AMSTAR Rating
Summary
Patient Population:
Eight randomized controlled trials (RCTs) with a total of 502 patients (average age of 60.11 years) were included in this study. All patients had a diagnosis of knee osteoarthritis (OA).
Intervention:
All RCTs had a regional injection of mesenchymal stem cells (MSC) without surgical treatment. One study (Freitag et al., 2019) compared one injection to two injections of MSC while the rest only had one intervention group receiving a single dose. While six studies had a fixed single dosage for participants, one study (Lamo-Espinosa et al., 2016) had two different dose groups receiving either high or low dosages, and another study (Chen et al., 2021) had three different dosage levels (16 million cells, versus 32 million cells, versus 64 million cells). Five studies injected adipose-derived MSCs (ADMSCs), and three studies injected bone marrow MSCs (BM-MSCs). Follow ups ranged between two weeks and 12 months post-injection.
Comparison:
All studies either had standard medication (hyaluronic acid injections) or placebo (saline injections) interventions for their control groups. Follow-up time periods and outcome measures were the same for control groups and intervention groups.
Outcome:
The primary outcome measure in this meta-analysis was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) to assess pain, stiffness and function. Additionally, the Visual Analog Score (VAS) for pain, Knee Injury and Osteoarthritis Outcome Score (KOOS), and adverse events were examined.
- At six months, the pain, stiffness, and functional subscales, as well as the total WOMAC scores all demonstrated statistically significant improvement in MSC groups compared to controls: (1.13; 95% CI: 0.45 to 1.81; P=0.001), (0.49; 95% CI: 0.11 to 0.86; P=0.01), (3.36; 95% CI: 0.98 to 5.73; P=0.006), and (7.44; 95% CI: 1.45 to 13.42; P=0.01) respectively.
- At 12 months, the pain and stiffness subscale, as well as total WOMAC scores demonstrated statistically significant improvement in MSC groups compared to controls: (1.03; 95% CI: 0.02 to 2.03; P=0.04), (0.65; 95% CI: 0.02 to 1.27; P=0.04), and (10.31; 95% CI: 0.96 to 19.67; P=0.03). There was no significant difference between the MSC and control groups at 12 months on the functional subscale (0.82; 95% CI: -4.33 to 5.97; P=0.76).
- A subgroup analysis of dosage examined low dose (1.0 x 107 – 6.4 x 107) and high dose groups (1.0 x 108 – 2.0 x 108) compared to controls. At six months, results showed significant improvement in high dose WOMAC scores compared to controls (8.14; 95% CI: 4.26 to 12.02; P=0.002), and insignificant differences between low dose and control groups (3.20; 95% CI: -1.29 to 7.68; P=0.16). At 12 months, both high and low dose groups showed significantly better improvements in WOMAC scores compared to controls: (14.25; 95% CI: 7.44 to 21.07; P<0.0001) and (4.84; 95% CI: 0.45 to 9.24; P=0.03) respectively.
- A subgroup analysis of cell sources demonstrated statistically significant improvement in ADMSC WOMAC scores compared to controls at six months (7.53; 95% CI: 4.42 to 10.63; P<0.00001) and 12 months (8.76; 95% CI: 4.35 to 13.16; P<0.0001). BM-MSC WOMAC scores compared to controls were found to be insignificant at six months (-6.30; 95% CI: -17.45 to 4.85; P=0.27) and 12 months (6.00; 95% CI: -3.32 to 15.31; P=0.21).
- VAS scores also significantly improved in MSC groups compared to controls at six months (19.39; 95% CI: 8.10 to 30.68; P=0.0008) and 12 months (16.21; 95% CI: 7.38 to 25.04; P=0.0003).
- There was no significant difference found between intervention and control groups adverse events (1.32; 95% CI: 0.85 to 2.05; P=0.21) and serious adverse events (0.78; 95% CI: 0.23 to 2.65; P=0.69).
Guideline Recommendations
| Source | Recommendation |
|---|---|
| ACR/Arthritis Foundation Guideline (2019) | Strong recommendation against |
| Arthritis Alliance of Canada/CFPC Osteoarthritis Tool (2017) | Inconclusive evidence |
| OARSI Guidelines (2019) | Strongly recommendation against |
Outcomes Assessed
- Benefit
- Harm
- Inconclusive
Pain and Stiffness
6 and 12 months
Function
6 and 12 months
Adipose Derived (ADMSC) v. Bone-Marrow Derived (BM-MSC)
ADMSC v. Placebo
BM-MSC v. Placebo
Relevant Clinical Info
Kim KI, Lee MC, Lee JH, Moon YW, Lee WS, Lee HJ, Hwang SC, In Y, Shon OJ, Bae KC, Song SJ, Park KK, Kim JH. Clinical Efficacy and Safety of the Intra-articular Injection of Autologous Adipose-Derived Mesenchymal Stem Cells for Knee Osteoarthritis: A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial. Am J Sports Med. 2023 Jul;51(9):2243-2253. doi: 10.1177/03635465231179223. Epub 2023 Jun 21. PMID: 37345256.
Kim et al. (2023) was found to have low risk of bias and was also the most recent and largest RCT included in this meta-analysis. With a total of 252 participants (Male= 65, Female= 187, average age of 63.75 years) living with grade III symptomatic knee OA, researchers were able to examine the effects of ADMSC compared to placebo injections in pain and functional outcomes. Patients in the intervention group were injected with autologous high-dose ADMSCs (1 x 108 ADMSCs; normal saline, 2.1 mL; autologous serum, 0.9 mL), while patients in the control group received normal saline (2.1 mL; autologous serum, 0.9 mL). Overall, ADMSC showed significantly stronger improvement in VAS scores compared to the control group at six months (11.8; 95% CI: 6.4 to 17.4; P<0.001). ADMSC total WOMAC scores were also significantly better than control scores at six months (8.9; 95% CI: 4.3 to 13.4; P<0.001). The ADMSC also achieved a significantly higher proportion of patients above the VAS minimal clinically important difference (MCID) at six months for 14 points of absolute improvement (ADMSC, 68.5%; control, 53.7%; P=0.19) and 20% relative improvement (ADMSC 75%; control, 60.5%; P=0.021). The same was found for ADMSC regarding WOMAC MCID at four months for nine points of absolute improvement (ADMSC, 73.4%; control, 47.6%; P=0.001) and 33% relative improvement (ADMSC, 61.3%; control, 45.2%; P=0.015). The authors did not find a significant radiological difference when comparing whole-organ magnetic resonance imaging scores (WORMS) at baseline and six months. While grade 1 and 2 adverse events did occur in both groups, the authors did not find a significant difference between their frequency.
Participant Information
The sample size was 502
Mean age of 60.11 years.
There were 8 studies used.
