title: 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).
abstract: 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 × 10(6) or 100 × 10(6) 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 × 10(6) cells are administered. These results pave the way for a future phase III clinical trial.
  
  
  
  gov identifier NCT02123368. Nº EudraCT: 2009-017624-72.
authors: Department of Orthopaedic Surgery and Traumatology, Clínica Universidad de Navarra, Pamplona, Spain.
authors: José M
authors: JM
authors: Lamo-Espinosa
authors: Department of Orthopaedic Surgery and Traumatology, Clínica Universidad de Navarra, Pamplona, Spain.
authors: Gonzalo
authors: G
authors: Mora
authors: Department of Orthopaedic Surgery and Traumatology, IBSAL-Hospital Universitario de Salamanca, Salamanca, Spain.|TerCel (Spanish Cell Therapy Network, Spanish National Institute of Health Carlos III), Madrid, Spain.
authors: Juan F
authors: JF
authors: Blanco
authors: Department of Orthopaedic Surgery and Traumatology, Clínica Universidad de Navarra, Pamplona, Spain.|TerCel (Spanish Cell Therapy Network, Spanish National Institute of Health Carlos III), Madrid, Spain.|Cell Therapy Area, Clínica Universidad de Navarra, Pamplona, Spain.|Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.
authors: Froilán
authors: F
authors: Granero-Moltó
authors: Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.|Division of Biostatistics, Research Support Service, Central Clinical Trials Unit, Clínica Universidad de Navarra, Pamplona, Spain.|Department of Preventive Medicine and Public Health, Medical School, University of Navarra, Pamplona, Spain.
authors: Jorge M
authors: JM
authors: Nuñez-Córdoba
authors: Department of Orthopaedic Surgery and Traumatology, Clínica Universidad de Navarra, Pamplona, Spain.
authors: Carmen
authors: C
authors: Sánchez-Echenique
authors: Department of Radiology, Clínica Universidad de Navarra, Pamplona, Spain.
authors: José M
authors: JM
authors: Bondía
authors: Department of Radiology, Clínica Universidad de Navarra, Pamplona, Spain.
authors: Jesús Dámaso
authors: JD
authors: Aquerreta
authors: TerCel (Spanish Cell Therapy Network, Spanish National Institute of Health Carlos III), Madrid, Spain.|Cell Therapy Area, Clínica Universidad de Navarra, Pamplona, Spain.
authors: Enrique J
authors: EJ
authors: Andreu
authors: Department of Rheumatology, Clínica Universidad de Navarra, Pamplona, Spain.
authors: Enrique
authors: E
authors: Ornilla
authors: TerCel (Spanish Cell Therapy Network, Spanish National Institute of Health Carlos III), Madrid, Spain.|Department of Hematology, IBSAL-Hospital Universitario de Salamanca, Salamanca, Spain.|Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Castilla y León, Salamanca, Spain.
authors: Eva M
authors: EM
authors: Villarón
authors: Department of Orthopaedic Surgery and Traumatology, Clínica Universidad de Navarra, Pamplona, Spain.
authors: Andrés
authors: A
authors: Valentí-Azcárate
authors: TerCel (Spanish Cell Therapy Network, Spanish National Institute of Health Carlos III), Madrid, Spain.|Department of Hematology, IBSAL-Hospital Universitario de Salamanca, Salamanca, Spain.|Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Castilla y León, Salamanca, Spain.
authors: Fermín
authors: F
authors: Sánchez-Guijo
authors: TerCel (Spanish Cell Therapy Network, Spanish National Institute of Health Carlos III), Madrid, Spain.|Department of Hematology, IBSAL-Hospital Universitario de Salamanca, Salamanca, Spain.|Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Castilla y León, Salamanca, Spain.
authors: María Consuelo
authors: MC
authors: Del Cañizo
authors: Department of Orthopaedic Surgery and Traumatology, Clínica Universidad de Navarra, Pamplona, Spain.
authors: Juan Ramón
authors: JR
authors: Valentí-Nin
authors: TerCel (Spanish Cell Therapy Network, Spanish National Institute of Health Carlos III), Madrid, Spain. fprosper@unav.es.|Cell Therapy Area, Clínica Universidad de Navarra, Pamplona, Spain. fprosper@unav.es.|Navarra Institute for Health Research (IdiSNA), Pamplona, Spain. fprosper@unav.es.|Department of Hematology, Clínica Universidad de Navarra, Avenida Pío XII 36, 31009, Pamplona, Navarra, Spain. fprosper@unav.es.
authors: Felipe
authors: F
authors: Prósper
mesh_terms: D000368:Aged; D003131:Combined Modality Therapy; D003710:Demography; D005260:Female; D006801:Humans; D006820:Hyaluronic Acid / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology*; D007270:Injections, Intra-Articular; D008279:Magnetic Resonance Imaging; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D016059:Range of Motion, Articular / Q000187:drug effects; D016896:Treatment Outcome; D064232:Visual Analog Scale
chemical_list: D006820:Hyaluronic Acid
keywords: Bone marrow-mesenchymal stromal cells; Knee osteoarthritis; Non-surgical management; Stem cell therapy