Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II)
Lamo-Espinosa JM (1), Mora G (1), Blanco JF (2,3), Granero-Moltó F (1,3,4,5), Nuñez-Córdoba JM (5,6,7), Sánchez-Echenique C (1), Bondía JM (8), Aquerreta JD (8), Andreu EJ (3,4), Ornilla E (9), Villarón EM (3,10,11), Valentí-Azcárate A (1), Sánchez-Guijo F (3,10,11), Del Cañizo MC (3,10,11), Valentí-Nin JR (1), Prósper F (12,13,14,15).
(1) Department of Orthopaedic Surgery and Traumatology, Clínica Universidad de Navarra, Pamplona, Spain.
(2) Department of Orthopaedic Surgery and Traumatology, IBSAL-Hospital Universitario de Salamanca, Salamanca, Spain.
(3) TerCel (Spanish Cell Therapy Network, Spanish National Institute of Health Carlos III), Madrid, Spain.
(4) Cell Therapy Area, Clínica Universidad de Navarra, Pamplona, Spain.
(5) Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.
(6) Division of Biostatistics, Research Support Service, Central Clinical Trials Unit, Clínica Universidad de Navarra, Pamplona, Spain.
(7) Department of Preventive Medicine and Public Health, Medical School, University of Navarra, Pamplona, Spain.
(8) Department of Radiology, Clínica Universidad de Navarra, Pamplona, Spain.
(9) Department of Rheumatology, Clínica Universidad de Navarra, Pamplona, Spain.
(10) Department of Hematology, IBSAL-Hospital Universitario de Salamanca, Salamanca, Spain.
(11) Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Castilla y León, Salamanca, Spain.
(12) TerCel (Spanish Cell Therapy Network, Spanish National Institute of Health Carlos III), Madrid, Spain.
(13) Cell Therapy Area, Clínica Universidad de Navarra, Pamplona, Spain.
(14) Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.
(15) Department of Hematology, Clínica Universidad de Navarra, Avenida Pío XII 36, 31009, Pamplona, Navarra, Spain.
Mesenchymal stromal cells are a promising option to treat knee osteoarthritis. Their safety and usefulness must be confirmed and the optimal dose established. We tested increasing doses of bone marrow mesenchymal stromal cells (BM-MSCs) in combination with hyaluronic acid in a randomized clinical trial.
A phase I/II multicenter randomized clinical trial with active control was conducted. Thirty patients diagnosed with knee OA were randomly assigned to intraarticularly administered hyaluronic acid alone (control), or together with 10 × 106 or 100 × 106 cultured autologous BM-MSCs, and followed up for 12 months.
Pain and function were assessed using VAS and WOMAC and by measuring the knee motion range. X-ray and magnetic resonance imaging analyses were performed to analyze joint damage.
No adverse effects were reported after BM-MSC administration or during follow-up. BM-MSC-administered patients improved according to VAS during all follow-up evaluations and median value (IQR) for control, low-dose and high-dose groups change from 5 (3, 7), 7 (5, 8) and 6 (4, 8) to 4 (3, 5), 2 (1, 3) and 2 (0,4) respectively at 12 months (low-dose vs control group p = 0.005 and high-dose vs control group p < 0.009).
BM-MSC-administered patients were also superior according to WOMAC, although improvement in control and low-dose patients could not be significantly sustained beyond 6 months. On the other hand, the BM-MSC high-dose group exhibited an improvement of 16.5 (12, 19) points at 12 months (p < 0.01).
Consistent with WOMAC and VAS values, motion ranges remained unaltered in the control group but improved at 12 months with BM-MSCs. X-ray revealed a reduction of the knee joint space width in the control group that was not seen in BM-MSCs high-dose group. MRI (WORMS protocol) showed that joint damage decreased only in the BM-MSC high-dose group, albeit slightly.
The single intraarticular injection of in vitro expanded autologous BM-MSCs together with HA is a safe and feasible procedure that results in a clinical and functional improvement of knee OA, especially when 100 × 106 cells are administered. These results pave the way for a future phase III clinical trial.
CITATION J Transl Med. 2016 Aug 26;14(1):246