The aim of this study was to document the available evidence on the use of regenerative techniques for the treatment of femoral head osteonecrosis (or avascular necrosis of femoral head, AVN) and to understand their benefit compared to core decompression (CD) alone in avoiding failure and the need for total hip replacement (THR).
The search was conducted on three medical electronic databases according to PRISMA guidelines. The studies reporting number and timing of failures were included in a meta-analysis calculating cumulative survivorship with a Kaplan-Mayer curve. Moreover, the results on failures in treatment groups reported in RCT were compared with those documented in control groups, in order to understand the benefit of biological therapies compared to CD for the treatment of AVN.
Forty-eight studies were included in this systematic review, reporting results of different types of regenerative techniques: mesenchymal stem cell implantation in the osteonecrotic area, intra-arterial infiltration with mesenchymal stem cells, implantation of bioactive molecules, or platelet-rich plasma. Overall, reported results were good, with a cumulative survivorship of 80% after ten year follow-up, and better results when regenerative treatments were combined to CD compared to CD alone (89.9% vs 70.6%, p < 0.0001).
Regenerative therapies offer good clinical results for the treatment of AVN. The combination of CD with regenerative techniques provides a significant improvement in terms of survivorship over time compared with CD alone. Further studies are needed to identify the best procedure and the most suitable patients to benefit from regenerative treatments for AVN.
Osteonecrosis of the femoral head or avascular necrosis (AVN) is a pathologic process that most commonly affects young adults in the third and fourth decades of their life. Its incidence is increasing, and every year, 10,000 to 20,000 new cases are diagnosed in the USA .
AVN can follow traumatic or non-traumatic conditions. The cause of atraumatic osteonecrosis of the femoral head is believed to be multifactorial, in some cases associated with both genetic predisposition and exposure to risk factors . These include, but are not limited to, corticosteroid use, alcohol abuse, previous trauma, haemoglobinopathy, Gaucher’s disease, and coagulopathies. The onset of AVN may also be idiopathic . Regardless of the specific initiating event, failure of perfusion may occur due to three mechanisms : vascular interruption, vascular occlusion, and extravascular compression. Any of these leads to a decreased blood supply/ischaemia in the femoral head. After a variable period of ischaemia, osteocyte, adipocyte, and haemopoietic marrow necrosis occurs, followed by a sequence of reactions and variable repair attempts . Although remodeling cycle continues in adjacent areas of bone with an intact blood supply and viable cells, bone resorption generally predominates, causing further weakening of subchondral bone, progressive collapse of subchondral trabeculae, and, ultimately, development of osteoarthritis .
It is estimated that 5–12% of total hip replacements (THRs) each year are performed to treat this disease , but their outcome has been shown to be less satisfactory compared to other indications, primarily due to the limited lifetime and durability of THR in such young patients [4, 5]. As a result, there is an increasing focus on the development of early interventions for AVN, aimed at preserving the native articulation to avoid or at least delay THR . Core decompression (CD) is currently the most widely accepted surgical treatment for early-stage AVN . The rationale of its use is to reduce or decompress the intraosseous pressure in the femoral head, resulting from venous congestion and other pathways, in order to promote vascular invasion and to facilitate regeneration of the necrotic tissue. However, the overall clinical success rate of CD has been shown to be only 63.5%, and the rate for subsequent THR or hip salvage surgery is about 33% . For this reason, its use has been debated  and, with the scope of improving CD results, the use of different regenerative techniques has recently been proposed to address early AVN stages.
The aim of this study was to document the available evidence on regenerative techniques in AVN with a systematic review, and to perform a meta-analysis of their results in preserving subchondral bone from collapse compared to CD, thereby avoiding failure and the need for THR.
Materials and methods
A systematic review of the literature was performed on biologic therapies for AVN. The search was conducted on June 23, 2017, using the following parameters on three medical electronic databases (PubMed, Scopus, and the Cochrane Collaboration): ((Stem cells) OR (bone marrow) OR (mesenchymal bone marrow) OR (biological therapies) OR (regenerative therapies)) AND ((femoral head surgery) OR (femoral head decompression) OR (hip decompression)) AND ((osteonecrosis) OR (necrosis) OR (bone marrow oedema) OR (bone marrow pathology)). The guidelines for Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) were used . Screening process and analysis were conducted separately by two independent observers (GM and SAA).
First, the articles were screened by title and abstract. The following inclusion criteria for relevant articles were used during this initial screening: clinical reports of any level of evidence, written in English language, with no time limitation, on biological regenerative therapies used to treat patients affected by hip AVN. Exclusion criteria were articles written in other languages, preclinical studies, reviews, or clinical studies analyzing non-biological techniques. In the second step, the full texts of the selected articles were screened, with further exclusions according to the previously described criteria. Furthermore, articles not reporting clinical outcome data were excluded. Reference lists from the selected papers were also screened. Relevant data (type of study, type of treatment, no. of patients, age of the patients, disease staging, aetiology, follow-up, results, complications, and failures) were then extracted and collected in a unique database with consensus of the two observers to be analyzed for the purposes of the present manuscript.
The primary aim of this review was to document through a qualitative analysis the different types of biological therapies applied in the clinical practice to treat hip AVN. Secondarily, the results of these procedures were further analyzed quantitatively, aiming at understanding their clinical potential in terms of survivorship and THR prevention compared to CD. To this aim, studies reporting number and timing of failures were selected, and the cumulative survivorship was analyzed with a Kaplan-Mayer analysis [9, 10]. Studies were included in the Kaplan-Mayer analysis only if they reported, for every single failure, either the specific time of revision to THR, or at least a failure time in an interval no longer than 2 years. Moreover, the results on failures in treatment groups reported in randomized controlled trials (RCTs) were compared with those documented in control groups, in order to understand the benefit of biological therapies compared to CD for the treatment of AVN.
The database search identified 713 records, and the abstracts were screened and selected according to the inclusion/exclusion criteria. As shown in Fig. 1, a total of 66 full-text articles were assessed for eligibility. Eighteen articles did not fulfill the criteria and were further excluded, leading to a total of 48 studies used for the qualitative analysis (a detailed description of these studies is reported in Table 1). As shown in Fig. 2, two thirds were published in the last four years, showing an increment in the interest on this surgical approach, whereas only 16 articles had been published in the previous 11 years. Overall, the evaluation of evidence level showed eight RCTs, two prospective comparative studies, seven retrospective comparative studies, 28 case series, and three case reports.
The biologic therapies analyzed in the included studies were heterogeneous, often applied in different combinations, mostly associated with the use of classic procedures (like CD or drilling), and sometimes associated bone substitutes (details of the specific procedures applied in each study are reported in Table 1). From a biologic point of view, four different types of treatment could be distinguished:
Stem cells applied in the osteonecrotic area: bone marrow-derived MSCs, mostly as bone marrow concentrate (BMC) [11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40], more rarely cultured [41,42,43,44,45] or simply as bone marrow aspirates [46, 47], adipose-tissue-derived MSCs , or allogeneic human umbilical cord-derived MSCs .
Intra-arterial injection of stem cells: the types of stem cells used with this approach were peripheral blood MSC mobilized by G-CSF , allogeneic human umbilical cord-derived MSCs , bone marrow-derived MSCs , or the combination of the last two methods .
The included studies also involved the use of different bone substitutes: autografts [21, 23, 25, 29, 54, 55, 58] (including also vascularized bone grafts [41,42,43]), allografts , xenografts , synthetic bone grafts, and scaffolds [27, 31, 34, 38, 45, 47, 57]. Metal constructs were also applied to reinforce bone architecture [42, 49, 50]. Some studies also combined pharmacological treatments, like intravenous iloprost  or oral bisphosphonates , hyaluronic acid , or physical therapy with low-intensity pulsed ultrasound .
These studies reported the results of AVN treatment in 2645 hips of 1988 patients. The populations included in the selected studies were very heterogeneous in terms of age, etiology, and AVN stage. Age presented a wide range: while mean age was around 35–45 years, patients ranged from children and teenagers to seniors. Only two studies analyzed specifically young populations, affected by sickle cell disease in one case  and by AVN after femoral neck fractures in the other . Etiology included steroid therapy (847 hips), alcohol (515 hips), sickle cell disease (446 hips), idiopathic (364 hips), trauma (121 hips), chemotherapy (8 hips), smoke (13 hips), immunosuppressive therapy (29 hips), HIV (10 hips), lupus (23 hips), pregnancy (1 hips), Cushing disease (1 hips), Caisson disease (11 hips), hepatitis C (3 hips), or other not specified etiologies (25 hips). AVN stage was evaluated with different systems: Association Research Circulation Osseous (ARCO) classification in 19 articles [11, 12, 15, 16, 19, 27, 29, 33, 35, 38, 39, 42,43,44, 50, 51, 53, 54], Ficat classification in 14 articles [13, 17, 20, 23,24,25, 28, 38, 46, 47, 49, 52, 55, 58], Japanese Orthopaedic Association (JOA) classification in 5 articles [14, 32, 34, 41, 57], Steinberg classification in seven articles [18, 22, 31, 36, 40, 41, 45], and Mitchell classification in one article . Overall, lesions of different stages, from early-stage AVN to collapsed head, were treated. Finally, evaluation time was also heterogeneous, with nine studies reporting short-term (< 24 months follow-up), 32 medium-term (24–60 months), and seven long-term results (> 60 months). The heterogeneity documented among studies may have influenced the results, as reported in some studies showing a better outcome for less severe and smaller lesions [21, 23, 29, 31, 40, 52, 54]. Other factors found to influence the final outcome were the number of transplanted cells [25, 36, 40] and etiology, with steroid-induced AVN showing poorer results [31, 40, 46] and traumatic AVN achieving better improvement than non-traumatic AVN .
Clinical results are reported in detail in Table 1. In summary, all 28 case series showed clinical score improvements, as well as good radiological and histological outcomes, with the only exceptions represented by the study by Chotivichit et al. , who showed short-term disease progression in 76% of the stage 2 and 69% of the stage 3 AVN after the injection of bone marrow aspirate, and the study by Kang et al. , who reported negative results in 26/61 hips at 68 months of follow-up.
Among comparative studies, seven were retrospective comparative studies [13, 15, 17, 25, 34, 54]: six missed to find any significant difference between treatment and control groups, analyzing clinical scores, radiologic outcomes and failures, and only one  reported significantly increased clinical and radiological scores, with fewer failures. Two level II prospective comparative studies [11, 39] were found in the literature. The study of Pilge et al.  performed a match-pair subanalysis of a RCT, but the number of patients was underpowered to obtain any significant difference. Conversely, Ganji et al. , although dealing with a very small survey of 18 hips, reported a significant increase in scores among patients treated with BMC, whereas patients treated only with CD did not significantly improve. Moreover, the failure rate of the treatment group was significantly lower than the control group.
The eight RCTs confirmed overall favourable results for the biological augmentation, with only two studies missing to find any significant difference. In detail, Pepke et al.  reported comparable clinical scores and failure rate, analyzing at two year’ follow-up 11 hips treated with CD and BMC implantation against 14 hips treated with CD alone. Rastogi et al.  compared 30 hips treated with CD and unprocessed bone marrow with 30 hips treated with CD and BMC implantation, finding a significant difference in radiological score, but none in clinical scores. The other six RCTs [19, 23, 30, 33, 44, 50] reported a higher improvement of clinical and radiological outcomes in the groups treated with biological augmentation (four studies with BMC, one study with cultured bone-marrow derived MSC, and one study with intra-arterial injection of peripheral blood MSC).
The meta-analysis of failures with the Kaplan-Mayer analysis among 1467 patients analyzed in 41 studies (excluding studies not reporting the number or the time of failures) showed a total estimated cumulative survivorship of 89.1% at 24 months of follow-up, 81.9% at 60 months of follow-up, and 80% at 120 months of follow-up, confirming overall good results and durability for biological therapies (Fig. 3).
Finally, in order to make a comparative evaluation of homogeneous treatment and control groups, a meta-analysis was performed including only level 1 RCT dealing with stem cell augmentation [16, 19, 23, 26, 30, 33, 44, 50]. The total estimated cumulative survivorship for biological therapies and control group was of 95.6 vs. 85.7% at 24 months of follow-up and 89.9 vs. 70.6% at 60 months of follow-up, with a statistically significant difference between the two curves (p < 0.0001, evaluated with the log rank method), showing the benefit of regenerative therapies compared to CD to provide longer lasting results for the treatment of AVN (Fig. 4).
The main finding of this study is that regenerative therapies offer a higher survivorship over time compared to control group for the treatment of AVN, as demonstrated by a level I meta-analysis.
This systematic review allowed to document several regenerative procedures. Biological therapies to address AVN were introduced in the clinical practice in the 1990s, aiming at improving the results of CD . In particular, stem cell-based therapies have been used with the rationale of enhancing the effect of core decompression by promoting bone formation in AVN . Different factors may explain the effectiveness of BMC [59, 60]: the presence of stem cells endowed with osteogenic properties, the secretion of angiogenic cytokines, resulting in increased angiogenesis and subsequent improvement in osteogenesis, as well as the presence of endothelial cell progenitors actively engaged in neoangiogenesis from the pre-existing capillaries and able to enhance the generation of pericytes and vascular mural cells .
Aside from BMC, this systematic review documented several other regenerative techniques, proposed in the last 20 years to improve AVN healing. These include implantation of other types of MSC (like adipose-tissue derived or allogeneic human umbilical cord-derived MSCs) in the osteonecrotic area, intra-arterial injection of MSCs, implantation of bioactive molecules (recombinant human bone morphogenetic protein or growth factors), and PRP. They were used to treat extremely heterogeneous AVN conditions in heterogeneous populations and, at the moment, no recommendation can be made on the most efficient treatment or on the best indications . Nevertheless, a meta-analysis of the survivorship curve among 1467 patients analyzed in 41 studies showed an overall total estimated cumulative survivorship of 80% at 120 months of follow-up, confirming good results and durability for the biological augmentation approach.
The interest in regenerative therapies for AVN is rising, with growing evidence provided by the increasing number of published case series, RCT, reviews, and meta-analysis, with particular focus on results of cell-based therapies. Literature evidence has been analyzed in the past few years, with several authors supporting the overall benefit both in term of clinical and radiological outcomes.
In 2014, Li et al.  published a meta-analysis including one RCT and one comparative study, reporting a significant improvement in clinical outcomes, evaluated with the Harris hip score (HHS). Later in the same year, Lau et al.  published a systematic review on five studies, including three RCTs reporting better clinical results, and two reporting better radiological results for CD and BMC compared to CD alone. In 2016, three meta-analyses were published on the use of cell therapy combined with CD for the treatment of AVN. Clinical results were analyzed by Yuan et al. , who included one RCT and three comparative studies and found a significant difference in HHS between treatment and control groups. They also demonstrated an improvement of radiological outcome, in terms of AVN progression, including six articles, two of which were RCT. This result was also confirmed by Villa et al.  on two RCT, and by Papakostidis et al. , who included three RCTs and three comparative studies to document a reduced rate of femoral head collapse. Finally, in a recent systematic review, Piuzzi et al.  included 11 comparative studies, 8 of which were RCTs. They concluded that cell therapies led to a significant clinical improvement in 7/11 comparative studies and a better radiological outcome in 8/11 studies.
While all the aforementioned literature reviews and analysis agree on an overall positive outcome in terms of symptomatic relief and functional improvement, reflected in the different clinical scores, and of radiographic appearance of the femoral heads after regenerative treatments, only a weaker evidence supported possible benefits in terms of failures. The reduction of the number of failures, defined as the need to undergo THR, can actually be considered the most important goal in this type of patients. In fact, the durability of THR is a concern in such young patients, with a considerable risk for revision arthroplasty during their lifetime. Therefore, the success of non-replacement procedures is of key importance both for patients’ quality of life and for the impact on the health care system and society.
Failures were analyzed in two systematic reviews, which reported that the majority of the current literature found a lower number of THR in patients treated with CD and cell therapy compared with patients treated with CD alone [4, 66]. Meta-analysis articles, however, were not able to provide strong evidence to confirm these findings. In fact, Villa et al.  included in the analysis two RCTs and were not able to find a significant difference. Similarly, Papakostidis et al.  performed a meta-analysis of failures on six comparative studies, but they only found a tendency for cell therapy against CD alone. Only Yuan et al.  were able to demonstrate a significant decrease in failures in hips treated with both CD and BMC, but with the limits of a meta-analysis including three retrospective comparative studies and therefore low study level. This is not of secondary importance, since a direct correlation between low study quality and positive results has been demonstrated in the literature .
The present study was able to document, for the first time with methodologically strong level I analysis, that the use of regenerative therapies can reduce the number of failures compared to CD alone. The Kaplan-Mayer method was used to perform a meta-analysis of eight level I RCTs in order to calculate and compare the survivorship of control and treatment groups. At medium-term follow-up, 89.9% of hips treated with CD and regenerative therapies survived, against 70.6% of hips treated with CD alone.
This meta-analysis still presents some limitations. The first one is represented by the heterogeneity of the populations analyzed, with heterogeneous lesion stages, etiologies, and patient characteristics. Anyway, this limit is overtaken in the level I meta-analysis that represents a comparison between control and treatment groups which were homogeneous inside the single RCT. However, residual heterogeneity among the whole populations does not allow to draw conclusions about patients who could get the maximum benefit from the procedures. Another methodological limitation is the inclusion of a time interval for failures, which limits the value of the survivorship curve in studies with short follow-up; nonetheless, this is not of primary matter for a treatment which is intended to last decades. Moreover, AVN was evaluated with different systems, which introduces variability in the interpretation of the results. Finally, the included studies described results of different treatments (even though the meta-analysis focused on RCT, all regarding stem cell-based therapies), which may have different success rates. In addition, there is a lack of homogeneity among control groups, sometimes chosen as CD alone, sometimes as CD plus not concentrated bone marrow aspirate. Indeed, at the present moment, the BMC approach itself lacks standardization with respect to the quantitative and qualitative characterization of methods for cell harvest, cell processing, and cell transplantation/delivery, as described in a recent review by Piuzzi et al. . Therefore, it is not possible to propose a regenerative therapy against the others, and neither there is evidence to understand if the ideal treatment could include more than one single therapy, creating a biologic chamber using the “diamond concept” for bone healing . Moreover, PEMF and hyperbaric oxygen therapy may represent suitable options for the earlier stages , and future studies should further explore their potential and treatment indication, alone or in combination with the emerging regenerative options. However, this analysis still allowed to draw interesting conclusions on the potential of biological treatments.
This systematic review documented a growing interest on regenerative therapies for the treatment of AVN. Overall, they offer good clinical results, with an overall survivorship rate of 80% at ten years. The level I meta-analysis showed that the combination of CD with regenerative techniques provides a significant improvement in terms of survivorship over time compared to CD alone. Further studies are needed to identify the best procedure and the most suitable patients to benefit from regenerative treatments for AVN.
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The authors thank Elettra Pignotti for the assistance in the statistical analysis and Lucia Mancini for English editing.
Conflict of interest
The authors declare that they have no conflict of interest.
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Andriolo, L., Merli, G., Tobar, C. et al. Regenerative therapies increase survivorship of avascular necrosis of the femoral head: a systematic review and meta-analysis. International Orthopaedics (SICOT) 42, 1689–1704 (2018). https://doi.org/10.1007/s00264-018-3787-0
- Avascular necrosis of femoral head
- Regenerative therapies
- Biological therapies
- Core decompression