Discussion

We evaluated the clinical outcomes of patients treated with osteoblast cell therapy following core decompression for ONFH (ARCO 2019) in multiple centers across India. The results of the study suggested meaningful improvements in pain intensity and functional capacity, as suggested by the significant mean change in VAS and HHS scores, which exceeded the presupposed MCID at a mean follow-up of 3.5 years. Furthermore, less than 10% of patients (or hips) underwent THA at follow-up, indicating that in young patients, osteoblast cell therapy was associated with slower disease progression, reduced pain, a clinically meaningful improvement in HHS, and delayed need for THA. The median THA-free survival was 78 months despite a small number of late events, and sensitivity analyses supported the robustness of the estimate.

Core decompression is the preferred approach, performed via drilling and eliminating the necrotic lesion. A retrospective single-center study examined the effectiveness of core decompression in 46 patients (65 hips) with an early stage of ONFH, classified according to the Ficat-Arlet staging system, and reported a significant and long-term palliative effect across all stages; however, prevention of disease progression was observed only in patients with stage I ONFH [22]. Similarly, another retrospective study reported a 58% success rate in 135 patients (207 hips) who underwent core decompression for pre-collapse stage (Ficat stages I and II) ONFH [23]. Furthermore, a meta-analysis of 20 studies and 2,123 hips reported improved clinical outcomes with the addition of stem cell therapy to core decompression in patients with ONFH [24]. Consistent with these findings, combining core decompression with regeneration therapy has been shown to accelerate healing and reduce the risk of femoral head collapse [25]. Consequently, core decompression with adjuvant implantation of orthobiologics has been introduced to address the cellular pathophysiology of ONFH.

Considering the altered number of MSCs in the hematopoietic tissue and stroma of the bone marrow in patients with osteonecrosis, it was hypothesized that implantation of ex vivo expanded autologous osteoblasts could enhance the tissue repair process, restore lost bone mass, and prevent disease progression [16]. It was found that bone alkaline phosphatase-characterized osteoblasts have greater regenerative potential compared with heterogeneous bone marrow cells [26,27]. Thus, osteoblast cell therapy could offer the advantages of biological augmentation of core decompression with the implantation of a precise number of osteoblasts (48-50 million cells per joint), which would further enhance the repair and regeneration process. Other advantages of this approach are as follows: (i) the osteoblasts are derived from the patient’s own harvested bone marrow, making the therapy safe for implantation; (ii) removal of necrotic bone creates more space for the formation of new bone; and (iii) the repair and regeneration process is further facilitated because the injected osteoblasts readily integrate with the immature bone tissue from adjacent tissue, while the organized hematoma developed at the decompression site provides a scaffold for the autologous cultured osteoblasts. Several studies have demonstrated the efficacy of implantation of ex vivo expanded autologous osteoblasts with core decompression across various stages of the disease and etiologies [17,28-35]

The results of the present study also indicated an improvement in functional outcomes with the combination of core decompression and osteoblast cell therapy, which is in accordance with the findings from previous research [16,17]. Results from a retrospective observational study showed an improvement in VAS scores from 58.8 ± 13.8 to 32.2 ± 32.1 and HHS scores from 47.1 ± 12.3 to 63.7 ± 27.7 in 61 patients (98 hips) at a mean follow-up of 6.3 years [16]. Recently, Patro et al. evaluated the efficacy of osteoblast cell therapy following core decompression for the treatment of ONFH in 26 patients at a 36-month follow-up [17]. Significant improvements in VAS scores (9.00 ± 0.00 vs 3.01 ± 0.03; p < 0.001) and HHS scores (46.12 ± 3.68 vs 89.23 ± 2.19; p < 0.001) were reported. MRI assessment demonstrated significant osteogenesis at the site of osteoblast cell therapy in 22 (out of 26) patients using MRI. The researcher also reported that the use of osteoblast cell therapy for ONFH treatment represents an innovative regenerative medicine approach aimed at promoting osteogenesis through differentiated osteoblast cells. A key strength of this method is the precise regulation of cell quantity and quality, which enhances the consistency and reliability of therapeutic outcomes [17]. In the present study, we also noted imaging findings suggestive of osteogenesis in the femoral head, with preservation of joint space sphericity, on postoperative MRI images of patients at 24-month and 36-month follow-ups. Furthermore, postoperative X‑ray images of different patients showed radiographic features consistent with osteogenesis at different time intervals. Hence, the present study supports the findings of the previous study that adjuvant osteoblast cell therapy with core decompression can lead to successful bone remodeling and integration of the implant with the host bone tissue [17].

The natural progression of the disease requires THA in up to 75% of patients, as reported in a retrospective study after a 10-year follow-up of patients with ONFH [36]. However, osteoblast cell therapy appears effective in reducing the need for THA [10]. In the present study, after a mean follow-up of 3.5 years, THA conversion was required for 8.8% of treated hips (9.7% of patients); the majority of hips that underwent THA were in stage III (13.95%) and had trauma, COVID-19, or alcohol-related etiologies, which is lower than previously reported [16]. Interestingly, a delay in treatment was a significant finding in our study, with each additional month of delay increasing the hazard of THA by 1.28. In comparison, a previous study reported THA conversion in 28.7% of hips at a mean follow-up of 6.3 years [16]. Also, the patient-to-patient heterogeneity in isolated MSCs could be due to age factor; however, this variability was partially mitigated in the present study through ex vivo expansion and osteogenic differentiation under standardized cell culture conditions, followed by a predefined minimal dose of 48 million viable osteoblast lineage cells transplanted. Therefore, no apparent age-related correlation with study outcomes was observed in the present study.

The major limitations of this study include its retrospective design and lack of a control group. The retrospective design increases the risk of selection bias and limits the ability to adjust for unmeasured confounders and may have contributed to the low reported rate of THA requirement. Moreover, the absence of a control or comparator group does not allow for drawing causal inferences regarding treatment outcomes. In addition, because osteoblast implantation was performed concomitantly with core decompression, the study design did not allow isolation of the independent therapeutic effect of osteoblast cell therapy or evaluation of its incremental benefit over core decompression alone. These limitations should be considered when interpreting the findings. Non-treatment factors such as lifestyle changes, rehabilitation, concurrent medications, or supportive care could have contributed to improvement, but these were not fully accounted for. The surgical procedure and radiological assessments were standardized; however, considering the multicenter nature of the study, methodological, radiological, and rehabilitative heterogeneity should also be considered, which may affect the uniformity of the outcomes. Quantitatively demonstrating application and adherence differences by center, along with incorporating the center effect into the model, would have enhanced the generalizability of the findings.

Given the inclusion of patients with ONFH from various etiological factors, there may be some variability in baseline patient characteristics. Particularly, patients with COVID-19 differed in infection severity and treatment exposure. VAS and HHS were recorded at the patient level and could not be uniquely attributed to individual hips in bilateral disease. Therefore, they were not directly modeled towards hip-level covariates. Since radiological assessment was not performed for all patients and quantitative analysis was unavailable, comprehensive evaluation of radiological disease progression and treatment response was limited. Our analysis suggests exponential effects for delay-to-treatment analysis, which are highly susceptible to confounding by indication and baseline severity; patients treated later may systematically differ in stage distribution, lesion characteristics, etiology, socioeconomic access, and preoperative function. Despite these limitations, the study provides supportive evidence of the efficacy and safety of osteoblast cell therapy for the treatment of ONFH.