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)

J Transl Med. 2016 Aug 26;14(1):246. doi: 10.1186/s12967-016-0998-2.


Background: 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.

Materials: 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.

Results: 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.

Conclusions: 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.

Clinical trials: gov identifier NCT02123368. Nº EudraCT: 2009-017624-72.

Keywords: Bone marrow-mesenchymal stromal cells; Knee osteoarthritis; Non-surgical management; Stem cell therapy.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Combined Modality Therapy
  • Demography
  • Female
  • Humans
  • Hyaluronic Acid / administration & dosage*
  • Hyaluronic Acid / adverse effects
  • Hyaluronic Acid / pharmacology*
  • Injections, Intra-Articular
  • Magnetic Resonance Imaging
  • Male
  • Mesenchymal Stem Cell Transplantation* / adverse effects
  • Middle Aged
  • Osteoarthritis, Knee / diagnostic imaging
  • Osteoarthritis, Knee / pathology
  • Osteoarthritis, Knee / physiopathology
  • Osteoarthritis, Knee / therapy*
  • Range of Motion, Articular / drug effects
  • Treatment Outcome
  • Visual Analog Scale


  • Hyaluronic Acid

Associated data