Background/Purpose: Non traumatic osteonecrosis (ON) of the femoral head is characterized by epiphyseal necrosis leading to femoral head collapse and eventually hip replacement. The physiopathology of ON is multifactorial but it can be seen as a vascular, mesenchymal and bone cells disease. The treatment of early stages ON of the femoral head is still controversial. Core decompression using single or multiple drillings demonstrated contradictory results. Moreover core decompression associated with the implantation of bone marrow concentrate (BMC) containing mesenchymal stem cells (MSC) showed encouraging results in prospective and controlled trials. Indeed, it could delay ON of the femoral head progression to fractural stages and improve symptoms. Then, the possibility was raised that a cell-based medicinal product (PREOB®) consisting in a population of autologous osteoblastic cells (OB) could be more efficacious than BMC for the treatment of early stages ON of the femoral head. This study was undertaken to evaluate the efficacy of OB cells implantation in a randomized comparison with BMC implantation in early stages (prefractural ARCO stage 1 or 2) ON of the femoral head.

Methods: Patients with stage 1 or 2 ON were included in a randomized controlled single blind trial. Hips were randomized to receive a core decompression procedure followed by BMC or OB cells implantation. In the BMC group, 410.6 ± 84.9 ml of bone marrow (BM) was harvested from the iliac crest and concentrated to 41.8 ± 10.9 ml. In the OB group, MSC were isolated from BM aspirate (56.8 ± 36.3 ml), expanded and differentiated ex vivo under autologous conditions to obtain a population of OB cells with a target of 20 million of OB cells. Hip pain (as measured by visual analogue scale), WOMAC® score and ARCO stage (as assessed by X-Rays) were evaluated at 3, 6, 12, 24 and 36 months. For the final radiological evaluation, all radiographs were and given a random number. Four readers assessed all blinded radiographs for the progression of ON from non-fractural (stage 1 or stage 2) to fractural stage of ON (stage 3 or 4) by reference to ARCO-defined stages. The primary endpoint was the proportion of treatment responders at 24 months. A responder was defined as the absence of progression to fractural stage (stage 3 or 4) and a clinically significant pain improvement (i.e., at least the MCID, namely ≥10mm from baseline).

Results: From 72 hips randomized, 63 hips were treated, and 60 hips (30 hips per group) were assessable and analyzed as the efficacy cohort. Baseline demographic data such age (50.2 ± 13.1 years), gender, BMI, risk factors (corticosteroids, alcohol abuse and idiopathic ON), location and size of ON (more than 50% in each group were extensive C lesion; >30%) and symptoms (pain score and WOMAC® score subscales) were not statistically different between groups. At 24 months, 70.0% versus 36.7% of hips (p=0.011) and at 36 months, 60.0% versus 33.3% of hips in OB and BMC groups respectively were considered as treatment responders. In post-hoc analysis, the rate of progression to stage 3 or 4 was in favor of the OB group: at 24 months, 20.0% versus 40.0% of hips and at 36 months, 20.0% versus 50.0% of hips in OB and BMC groups respectively progressed to stage 3 or 4 (corresponding to a 60% reduction in hip fracture; p<0.05). Over the 36-month period, the survival analysis showed a significant difference in the time to progression to stage 3-4 in favor of the OB group (Kaplan Meier; hazard ratio 0.37). In the OB group, the decrease in hip pain was clinically significant at all time points, and as early as 3 months, while no pain relief was observed in the BMC group. Finally, patients treated with OB cells demonstrated a decrease in joint symptoms at all time points according to the WOMAC® score. At 36 months, 3 hips in the OB group and 6 hips in the BMC group had undergone total hip replacement. Overall, 553 treatment emergent adverse events (TEAE) (226 in the BMC group and 327 in the OB group) were reported, of which 2.7% (15 TEAE) were possibly related to the procedure or the cell therapy products. 61.9% of subjects experienced at least one serious adverse event (SAE) during the study: 128 SAE (57 in the BMC group and 71 in the OB group) were reported in 39 hips (19 hips in the BMC group and 20 hips in the OB group).

Conclusion:  This is the first trial studying the efficacy of a differentiated bone cell therapy product in ON of the femoral head. Compared to BMC, PREOB® is well characterized and its ability to form bone well defined which might explained its superiority to BMC. This study showed that OB cells implantation could be more efficacious than BMC treatment to delay the progression to subchondral fracture stage (ARCO stage 3) and to reduce pain in ON of the femoral head

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/autologous-osteoblastic-cells-versus-concentrated-bone-marrow-implantation-in-osteonecrosis-of-the-femoral-head-a-randomized-controlled-single-blind-study/