The Role of Cell Therapies for the Treatment of Osteonecrosis of the Femoral Head

Abstract

Background:

Osteonecrosis of the femoral head (ONFH) can cause pain, diminished function, and eventual articular collapse, disproportionately impacting younger patients. Core decompression (CD) is used to halt or at least delay postcollapse disease in patients who suffer from ONFH, but it can have variable outcomes. Orthobiologics are cellular therapies, growth factors, and biomaterial substances obtained from human cells and tissue that promote biological healing and have recently gained attention in the treatment of osteonecrosis. In this review, the role of orthobiologics in the treatment of osteonecrosis is discussed.

Methods:

We reviewed the existing literature regarding orthobiologics in the treatment of precollapse ONFH. A total of 11 studies were included, consisting of six randomized controlled trials and five retrospective reviews. The included literature was obtained through a PubMed query of all studies from 1990 to 2024 that evaluated the role of ancillary cell-based therapies in the treatment of precollapse ONFH. Level IV and non-human studies were not included.

Results:

There were seven studies that supported the use of orthobiologics as an augmentation strategy to CD in terms of radiographic outcomes (i.e., prevention of femoral head collapse), clinical symptoms, or conversion to total hip arthroplasty. There were four studies (one retrospective review and three randomized controlled trials) that found no clinical or radiographic difference in collapse progression in patients who received CD versus CD along with an orthobiologic augmentation strategy.

Conclusions:

In summary, further adequately powered, multicenter, blinded, randomized controlled trials are necessary. In addition, many of the studies had other limitations, including a large variability in mesenchymal cell content and standardization. Although the current literature regarding orthobiologic augmentation in the treatment of precollapse ONFH appears promising, further investigation is necessary to conclude its efficacy.

Osteonecrosis of the femoral head (ONFH) primarily affects younger adults and is characterized by pain, diminished function, and eventual articular surface collapse [1,2]. Once the femoral head collapse occurs, arthritis of the joint space subsequently develops. At this stage of ONFH, the most reliable option to improve function and alleviate pain remains total hip arthroplasty (THA) [3,4]. Approximately 20,000 to 30,000 patients are diagnosed with ONFH annually, accounting for nearly 10% of the annual THAs performed in the United States [5,6]. Core decompression (CD) has been used in the precollapse stages of ONFH in attempts to halt or at least delay the progression to postcollapse disease and subsequent need for THA [7,8]. Given the varying success of CD alone, additional attempts have been made to alter precollapse disease progression with orthobiologics. Orthobiologics are substances obtained from human cells and tissue that promote healing [9]. An example of an orthobiologic is autologous bone marrow aspirate concentrate (BMAC), which can be harvested from various surgical sites based on the location of the recipient site (Figure 1) [10]. There are several clinical trials that have evaluated the role of BMAC as an adjuvant therapy to CD in the treatment of precollapse ONFH, but given the heterogeneous trial designs, the optimal treatment of precollapse ONFH remains to be determined. The goals of this review were to review the role of orthobiologics in the treatment of osteonecrosis, describe the relevant literature on precollapse ONFH and orthobiologics, and discuss future investigations on the treatment of precollapse ONFH.

Figure 1.

The use of bone marrow aspirate concentrate in the treatment of osteonecrosis of the femoral head.

Differences Between Mesenchymal Stem Cells and BMAC

Mesenchymal stem cells (MSCs) are cells with self-renewal capabilities that can differentiate into multiple cell types, including bone, cartilage, adipose, and other mesenchymal tissues [11,12]. Specifically, MSCs belong to a subset of mesenchymal lineage cells defined by the cell surface markers CD90+, CD105+, CD45−, CD35−, and CD73+ that can be isolated from fibroblast-like plastic adherent cells that are more generally referred to as mesenchymal stromal cells [13]. Due to their regenerative and differentiation potential, MSCs have been studied as a form of cell therapy for the treatment of various orthopaedic conditions, including osteoarthritis [14] and healing of bone defects, fracture nonunions [15], and osteonecrosis. Several meta-analyses reported that injection of bone marrow–derived MSCs into the CD track achieved better clinical outcomes, including the Harris Hip Score, reduction in the collapse of the femoral head, and need for total hip arthroplasty, compared to CD alone for early-stage osteonecrosis of the hip [16–18].

Although MSCs possess the capacity to differentiate into osteoblasts to form bone, this process is largely regulated by biological signals, including cytokines, growth factors, and chemokines originating from immune cells of the hematopoietic lineage from other immune cells. The BMACs provide critical additional biological cues to the site of CD to activate MSCs and thereby facilitate bone regeneration. The BMACs typically contain only 0.01% of MSCs and larger percentages of other immune cells, including neutrophils, monocytes, macrophages, and lymphocytes, in variable compositions among different individuals. These cells polarize to different phenotypes to create a proinflammatory (characterized by M1 macrophages, Th1 and Th17 lymphocytes) or antiinflammatory (including M2 macrophages, Th2 and Treg lymphocytes) environment [19,20]. The MSCs also possess an immune modulatory role; the crosstalk among MSCs and different immune cells defines the inflammatory state of the healing microenvironment.

Role of Orthobiologics in the Treatment of Osteonecrosis

Orthopaedic surgery has historically relied on the assistance of implants to provide stability, reconstruct degenerative joints, and provide osteoligamentous fixation during soft-tissue reconstructive or reparative procedures. In recent years, special attention has been paid to improving biological healing as an adjuvant to conventional orthopaedic interventions. Orthobiologics have grown in popularity given their potential as a biological solution to assist in the healing of musculoskeletal tissues [21]. Common examples of orthobiologics include platelet-rich plasma, BMAC, growth factors, and adipose-derived MSCs, among others [9]. Orthobiologics may be used in isolation or combined with other substances to improve musculoskeletal healing, especially for disease states where the current standard of care delivers less-than-ideal outcomes. These biologic augmentation strategies have been used to treat a wide variety of musculoskeletal conditions, ranging from osteoarthritis of the hip and knee to osteonecrosis [9].

Patients who suffer from ONFH are typically younger than those who suffer from primary osteoarthritis of the hip [22]. Once ONFH progresses to articular surface collapse, degenerative secondary arthritis occurs and may cause severe pain and functional disability. In postcollapse ONFH, the most reliable option to improve pain and function is THA [23]. To avoid the lifelong need for THA in these relatively young patients, interventions that promote the preservation of the hip joint and prevent or delay postcollapse disease remain the goal for patients who have precollapse ONFH. These patients have historically been treated with CD, as this is thought to incite a local inflammatory response in the femoral head and promote revascularization and bony remodeling [24]. However, the inflammatory response from CD alone is not always sufficient for adequate healing, and as such, adjuvant therapies such as orthobiologics are being investigated as an additional therapy in the treatment of precollapse ONFH.

The rationale for including orthobiologics in CD in the treatment of patients who suffer from precollapse ONFH involves optimization of the local environment for biological healing [25]. These augmentation products can be delivered directly to the primary lesion in ONFH through the previously established CD path [26]. As such, the addition of these autologous or allogenic products to the local microenvironment is thought to promote both osteoinductive and osteogenic pathways that improve osseous healing and remodeling [27]. Although there have been attempts to investigate the adjuvant use of orthobiologics for the treatment of precollapse disease ONFH, there remains a lack of appropriately powered randomized controlled trials to definitely determine their efficacy.

Current Limitations

Despite growing interest in orthobiologics, several limitations should be considered. Cost remains a barrier for widespread implementation, as many orthobiologics are not covered by third-party insurance. As such, there is a wide variation in cost to patients for these therapies, as insurance companies do not participate in the mediation of pricing [28]. In addition, the regulatory status of these therapies must also be reviewed. Orthobiologics fall under Code of Federal Regulations Title 21, Part 1,271. The Food and Drug Administration requires that autologous materials be “minimally manipulated” so as not to alter the biological characteristics of these materials [29]. Regarding BMAC, centrifugation is permitted as it does not alter its biological characteristics. However, the regulatory status of a particular orthobiologic may vary depending on how the tissues or cells must be manipulated during processing [29]. Although there is literature to support the use of cell-based therapies in the treatment of conditions like ONFH, a high-quality, well-powered, randomized clinical trial still needs to be performed to establish standardized protocols and to more clearly delineate who may receive the greatest benefit from cell-based therapies. Further research efforts will also need to account for the variability in MSC content with the use of BMAC for the treatment of ONFH.

Literature Review

A review of the pertinent literature relating to the role of orthobiologics in the treatment of precollapse ONFH is summarized in Table 1. A total of 11 studies were included, consisting of six randomized controlled trials and five retrospective reviews. The included literature was obtained through a PubMed query of all studies from 1990 to 2024 that evaluated the role of ancillary cell-based therapies in the treatment of precollapse ONFH. Level IV and nonhuman studies were not included.

Table 1.

Literature Summary of Orthobiologics for the Treatment of Precollapse Osteonecrosis of the Femoral Head.

Author/Year	Mean Age (Years)	Mean Follow-Up (Months)	Treatment and Control(s) (Total Cases/Hips)	Necrosis Severity Classification (Total Cases/Hips)	Patient-Reported Outcomes	Radiographic Outcomes	Conversion to THA
Gangji et al. 2011 [30]a	45.7 42.2	60	CD (11) CD + BMAC (13)	ARCO I (4) ARCO II (20)	Improved VAS pain and Lequesne Index scores in the BMAC group	The BMAC group was significantly less likely to progress to collapse.	No difference in time to conversion to arthroplasty
Sen et al. 2012 [31]a	NR	24	CD (25) CD + BMAC (26)	ARCO I-II (51)	The BMAC group had significantly better Harris Hip Scores.	No significant differences between treatment groups	Patients who received BMAC had significantly better hip survival, but rates of THA were not reported.
Zhao et al. 2012 [32]a	33.8 32.7	60	CD (51) CD + BMAC (53)	ARCO I (5) ARCO II (99)	The BMAC group had significantly improved Harris Hip Scores.	The BMAC group had significantly decreased volume of the femoral head involvement in hips subcategorized as stages IC, IIB, and IIC.	Five patients underwent THA in the CD-only group and none in the BMAC group.
Liu et al. 2013 [33]b	38.1 38.0	12 to 40	CD + HA + bone filler (27)CD + HA + bone filler + BMAC (28)	ARCO II (55)	Significantly improved Harris Hip and VAS pain scores in the BMAC group	Femoral head collapse was significantly less common in the BMAC group.	NR
Pepke et al. 2016 [34]a	44.5 44.3	24	CD (14) CD + BMAC (11)	ARCO II (25)	No significant difference in Harris hip scores between two groups	No significant differences in radiographic disease progression between groups	NR
Pardos et al. 2016 [35]b	36.7 42.6	45	CD (19) CD + BMAC (41)	Ficat I — II (60)	Postoperative Merlé D’Aubigne and Postel Hip Scores were similar in both groups.	No significant difference in radiographic collapse between groups	No significant difference between groups
Ulusoy et al. 2023 [36]b	39.3 38.4	32	CD (25) CD + BMAC (19)	Steinberg 1 (21) Steinberg 2 (23)	Patients who received BMAC over CD alone had significantly improved Harris Hip Scores.	NR	No patients underwent THA in the BMAC group, but two patients required THA in the non-BMAC group.
Hernigou et al. 2024 [37]b	41 (Overall)	8	CD (52) CD + washing effect (50) CD + MSCs (234)	ARCO I-II (336)	NR	Bone repair volume on MRI increased with an increased number of injected cells.	NR
Hauzeur et al. 2020 [38]a	50 51	36 36	CD + BMAC (26) CD + Osteoblastic cell therapy (30)	ARCO I (20) ARCO II (33)	No significant difference in WOMAC scores between groups	No significant difference in radiographic progression	No significant difference in THA rates
Hernigou et al. 2023 [39]b	34	120	CD (1,373) CD + autologous cell therapy (3,021) Control hips without intervention (764)	ARCO IA (1,317) IB (1,374) ARCO IC (185) ARCO IIA (1,563) ARCO IIB (1757) ARCO IIC (243)	NR	Of those who received cell therapy, 65% were collapse-free at 10 y versus 33% in CD alone versus 15% of hips without intervention.	NR
Jayankura et al. 2023 [40]a	45 46	18 17	CD + saline (30) CD + osteoblastic cell therapy (34)	ARCO I (21) ARCO II (43)	No significant difference in WOMAC scores at 12 mo between groups.	No significant difference in radiographic progression at 12 mo between groups	No significant difference in THA rates between groups

CD, core decompression; BMAC, bone marrow aspirate concentrate; NR, not reported; ARCO, Association Research Circulation Osseous; THA, total hip arthroplasty; MRI, magnetic resonance imaging; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index; VAS, visual analog scale; HA, hydroxyapatite; MSCs, mesenchymal stem cells.

^aRandomized controlled trial.

^bRetrospective review.

Results

Of the evaluated literature, seven studies supported the use of orthobiologics as an augmentation strategy to CD in terms of radiographic outcomes (i.e., prevention of femoral head collapse), clinical symptoms, or conversion to THA. There were four studies (one retrospective review and three randomized controlled trials) that found no clinical or radiographic difference in collapse progression in patients who received CD versus CD along with an orthobiologic augmentation strategy. There were six studies that evaluated the rates of conversion to THA [30,32,35,36,38,40]. A brief pooled summary was performed to determine overall rates of conversion to THA. In the pooled treatment group, there were 32 of 186 total patients who underwent THA, representing a conversion rate of 17.2%. In the pooled control group, there were 26 of a total of 166 patients who underwent THA, representing a conversion rate of 15.7%.

Of the seven studies in support of orthobiologics, the number of evaluated hips ranged from 24 to over 5,000 [30–33,36,37,39]. Of the four studies that found no clinical or radiographic difference, the number of evaluated hips ranged from 25 to 64 [34,35,38,40]. Of these four studies that found no difference in CD alone versus CD supplemented with an orthobiologic, there was concern that three investigations were underpowered to adequately assess their primary outcome. There was methodological heterogeneity regarding patient-reported outcome measures, mean follow-ups, and control groups. As summarized in Table 1, patient-reported outcome measures varied by study and included the Western Ontario and McMaster Universities Osteoarthritis Index, visual analog scale for pain, Harris Hip Scores, Merlé D’Aubigne and Postel Hip Scores, and Lequesne Index scores. Mean follow-up ranged from eight to 120 months. Control groups varied and consisted of either CD alone, CD with saline, or control hips without intervention. These nuances should be considered when considering the available literature.

In summary, further adequately powered, multicenter, blinded, randomized controlled trials are necessary. In addition, many of the studies had other limitations, including a large variability in the mesenchymal cell content and standardization.

Future Investigation

In attempts to determine if orthobiologics can improve clinical and radiographic outcomes in patients who suffer from precollapse ONFH, the “Autologous Bone Marrow Aspirate Treatment for Early-Stage Osteonecrosis” or “BATON” trial has been developed. This multicenter, blinded, randomized controlled trial seeks to determine the efficacy of CD alone versus CD with autogenous BMAC in patients who suffer from precollapse ONFH. The primary outcomes of this trial will include patient-reported visual analog scale pain scores, radiologic progression of osteonecrosis, and time to femoral head collapse. Secondary outcomes will include patient-reported outcome measures throughout the study’s duration, in addition to cellular characterization of the BMAC used to augment CD. The overall goal of this trial is to determine the efficacy of BMAC supplementation to CD in preventing postcollapse ONFH and improving patient symptoms.

Conclusions

Preventing postcollapse disease in patients who suffer from ONFH remains a challenge that requires novel therapies and further investigation. There were seven studies that supported the use of orthobiologics in addition to CD in terms of radiographic outcomes, clinical symptoms, or conversion to THA. There were four studies that found no clinical or radiographic difference in collapse progression for those who received CD versus CD along with an orthobiologic. Although the role of orthobiologics as a potential solution appears promising, further adequately powered, long-term investigation is currently in development to determine the efficacy of orthobiologics in the treatment of precollapse ONFH.