Background
Avascular necrosis (AVN) of the femoral head (FH) is a debilitating and painful disease with multiple etiologic risk factors [
1‐
4]. These include, but are not limited to, corticosteroid use [
1,
3‐
6], alcohol abuse [
1‐
4], previous trauma [
1,
3], hemoglobinopathy [
7], Gaucher’s disease and coagulopathies [
8]. The onset of AVN may also be idiopathic [
7]. AVN of the FH most commonly affects younger or middle aged adults [
2,
9,
10]. Disease progression commonly leads to collapse of the affected FH and ultimately, development of osteoarthritis [
1,
3,
4,
7,
11,
12]. Outcomes of THA for these younger and more active patients have been poor, primarily due to the limited lifetime and durability of total hip arthroplasty (THA) [
6,
10,
11]. As a result, there has been an increased focus on early-interventions for AVN, aimed at preservation of the native articulation [
6,
12]. Core decompression (CD) is currently the most widely accepted treatment for early-stage AVN of the FH; however, due to limited efficacy, its use has been debated [
12]. The development of safe, cost-effective, and potentially minimally invasive joint preserving treatments for early stage (precollapse) AVN merits further investigation.
Several studies, both clinical and pre-clinical, have demonstrated the efficacy of stem cells (SC) for the treatment of AVN of the FH [
1,
3,
11,
13‐
15]. SC can be obtained from a variety of sources, including autologous bone marrow [
2,
4,
10,
11,
16,
17], adipose tissue [
10] and dental-pulp [
4]. SC have been shown to promote bone formation [
4,
6,
11,
12] and neovascularization [
6,
11] in vitro. Additionally, patients treated with SC in conjunction with CD demonstrated significant improvements in Harris Hip Scores (HHS) [
15] as well as decreased hip pain and symptoms compared to those treated with CD alone [
2]. Yan et al. documented that stem cells implanted into the necrotic FH not only survive, but thrive and proliferate [
15]. Although the pathogenesis of AVN is unclear [
17] many hypothesize that SC work to improve early stage AVN potentially as a function of their critical role in the regulation and improvement of osteogenesis and angiogenesis [
11,
12]. Furthermore, it is thought that mesenchymal SC implanted into the necrotic FH may differentiate into osteoblasts or vascular endothelial cells, thereby promoting bone repair and regeneration [
12]. Despite encouraging results in preclinical (basic science) and clinical studies, improvements in hip survivorship or time to THA has not been uniformly reported and remains controversial [
2,
8,
14].
The purpose of our study was to perform a systematic review of the current medical literature on the treatment of early stage AVN of the FH using SC implanted via CD. We examined both preclinical studies and clinical studies. We reported bone healing outcomes (histologic and imaging outcomes) from preclinical papers and all examined outcomes from available clinical papers.
Methods
Eligibility criteria
Manuscripts were deemed eligible for our review if they evaluated treatment of early stage AVN of the FH with SC implanted via CD. We defined early stage AVN as precollapse of the FH. Both clinical and preclinical manuscripts were selected. For clinical trials, we included studies on patients age > 18. All types of clinical studies were eligible for inclusion to this review. Studies of all languages were eligible for inclusion to this review. For studies reporting on the same group of patients at multiple follow up periods, the most recent publication was used in this review. For preclinical studies, manuscripts were eligible if they examined bone healing either histologically, or by imaging techniques. If studies examined other treatments such as vascularized fibular grafting or bone morphogenic proteins, they were excluded unless the data on SC and CD were presented separately from the other treatments, to allow us to examine the effect of SC specifically.
Study identification
A systematic, computerized search for potential manuscripts was performed by three independent reviewers (HE, SM, RL). Pubmed (−July 2012), Ovid Medline (−July 2012) and EMBASE (−July 2012) databases were used to identify studies. Key words used for the search were: AVN or avascular necrosis or osteonecrosis AND stem cells; AVN or avascular necrosis or osteonecrosis AND autologous bone marrow. Abstracts were retrieved for all manuscripts considered relevant by title. Abstracts were independently reviewed and any disagreements were resolved by discussion. Full length articles of relevant abstracts were reviewed for inclusion. Bibliographies of the full length articles were also searched for other potential studies and full length articles were retrieved.
Outcomes data were extracted by two reviewers (HE, RL) using prearranged summary tables. Data extraction for preclinical studies included study design, animal model, type of SC used, sample size, and outcomes measured. For the clinical studies, study type, sample size, potential biases, AVN classification, AVN etiology, SC dose and cell type, and outcomes measured were recorded.
Discussion
This review systematically examined the current literature on SC therapy for the treatment of early stage (precollapse) AVN of the FH including clinical and preclinical studies. Preclinical studies yielded encouraging results for treatment of AVN of the FH with SC. Although the source of SC varied among studies, SC treatment of AVN uniformly demonstrated improvements in osteogenesis and vascularization. All 11 studies showed positive effects with respect to bone formation in groups treated with SC. Furthermore, reported X-ray, SPECT, CT and MR outcomes from all studies favoured the SC treatment group. Bone marrow was the most common source of SC but other sources such as adipose and dental pulp were identified. SC isolated from dental pulp represents a relatively new treatment option with noteworthy potential for use in orthopaedics [
4]. Adipose derived SC are another potential alternative to SC from bone marrow. Advantages of adipose derived SC include abundance, ease of isolation, rapid expansion, and multipotency [
10].
Despite positive results, relevance of animal models described in preclinical studies should be considered. Corticosteroid and liquid nitrogen induced AVN of the FH are widely recognized means for induction of AVN in numerous animal models; both lead to ischemic conditions within the FM and eventual osseous infarction producing changes phenotypically similar and clinically relevant to human disease [
36]. Some studies, however, have addressed the significance of larger animal models, particularly with respect to translational medicine, as they may better replicate conditions in human AVN. An ovine model of AVN of the FH may better reflect articulation in early-stage human AVN as compared to other disease models [
4]. For liquid nitrogen induced disease, the bone defect produced, which is non-negligible in animals with small diameter FHs, has been proposed as a limitation due to its absence from human pathology. This has led some researchers to reject use of this method on rabbits [
37].
Results of clinical studies were also encouraging. In our review, the clinical studies used CD as a means for implanting SC directly into the necrotic region of the FH, in the form of a cell suspension. CD works by decreasing intra-osseous pressure and improving circulation and vascularization [
9]. Used alone, however, CD exhibits inconsistent outcomes including poor lesion reconstruction, ultimately leading to FH collapse [
9,
14]. The progression of AVN of the FH occurs in consequence of a limited capacity for articular tissue self-repair [
3,
11,
14], including decreased osteogenesis [
11,
14] and vascularization [
3]. This may occur as a result of inadequate numbers of progenitor cells in the proximal femur of patients with AVN of the FH [
38]. It is thought that SC implanted into the necrotic region of the FH work to repopulate the low numbers of progenitor cells [
20]. Pluripotent, mesenchymal SC differentiate into various cell types, namely osteoblasts, thereby improving repair mechanisms and potentially reversing damage to bone [
11,
12,
14]. In addition to directly increasing bone formation by differentiating into osteoblasts, it is hypothesized that mesenchymal SC have an indirect effect by the expression of cytokines which influence osteogenesis and neovascularization [
39,
40]. In general, clinical studies reported improvements in patient reported outcomes for those treated with SC; notably, the HHS. Similarly, studies that examined progression to more advanced disease, and lesion volume reported improvements for the SC treatment group. Participants treated with SC did not experience consistent improvements in hip survivorship across studies. None of the studies using a comparative group found worse outcomes for SC treatment.
Considerable variations and inconsistent reporting among clinical studies were observed regarding the dose of SC, etiology of AVN, lesion size, and severity/classification of disease making comparisons between studies challenging. However, there are currently limited numbers of clinical studies addressing SC therapy for treatment of AVN of the FH, and even fewer addressing early-stage disease and administration of SC by CD. Accordingly, we were unable to perform meta-analysis on study results. Quantitative assessment will be a prerequisite to making definitive conclusions on vital therapy-related factors such as SC dose and quality.
Standardization of SC dose has proven difficult due to a lack of uniformly accepted, reliable cell markers which can be used to identify mesenchymal SC [
39]. However, the dose of SC used has been reported to impact disease outcome [
7]. Both SC dose and quality are also known to affect their clinical potential. Density of SC transplanted to the necrotic FH was shown to affect the rate of osteogenesis, and thereby bone repair [
12]. Quality of transplanted cells affects their proliferative capacity [
41]. Prior to routine use of combined SC/CD therapy, defined standards of SC dose and quality, such as CD34+ or CFU counts [
42], will likely have to be set in order to accurately evaluate the effect of each therapy. However, as a result of presently observed inconsistencies, and a paucity of studies in this area, further research, examining both SC dose and quality will be prerequisite to routine clinical use of this therapy.
Though not specifically addressed by studies assessed in this review, the impact on treatment outcome of whether cells were derived from a concentrate or a culture may also represent an area for future research. Pre-clinical and clinical studies included examples of both concentrated and cultured cells. Concentrated cells contain all cells and cell types present in the tissue from which they have been derived, not only SC. Concentrated BMMNC from bone marrow aspirate contain hematopoietic progenitor cells, lymphocytes, leucocytes, in addition to non-hematopoietic cells including MSC, EPC, embryonic-like SC expressing pluripotent markers, and other multipotent or committed cells [
43]. Cultured cells, conversely, represent an isolated pool of SC. The comparative regenerative capacity of concentrated vs. cultured cells remains unclear. Despite positive results observed for both treatments within this review, other studies explicitly assessing differences between the two have displayed mixed findings. Use of pure, cultured MSC led to greater improvements in ischemic limb diseases, compared to concentrated BMMNC, in both human and rat models [
44,
45]. Alternatively, BMMNC use displayed beneficial outcomes in treatment of spinal cord injury when compared to MSC [
46]. Cost and feasibility must also be considered when selecting an appropriate treatment. Indeed, cultured cells require greater preparation times and are associated with increased cost [
44,
47]. Ultimately, the outcomes of concentrated vs. cultured cells should be assessed for the specific treatment of AVN of the FH in order to develop future robust clinical guidelines for cellular intervention in this disease.
Etiologic risk factors of AVN are also known to significantly affect treatment outcomes [
2]. It has been demonstrated that the capacity for SC to differentiate into the necessary osteogenic cells for bone repair and remodeling is limited in patients with alcohol and steroid induced AVN of the FH due to differences in the ischemic environment [
12,
48]. The size of the osteonecrotic lesion is also known to affect overall patient outcome no matter the method of treatment used [
8,
49]. Future studies should aim to use the same AVN classification system as well as account for AVN etiology and lesion size as potential confounding variables.
Several other reviews [
18,
38,
50‐
53] have been published discussing the use of SC for the treatment of AVN of the femoral head. However to our knowledge, ours is the first systematic review that includes data from several recently published clinical trials [
2,
8,
14]. Our review included data from over 700 hips, more than previously published reviews. Additionally, our review included both clinical and pre-clinical studies, furthering the breadth of our review. A limitation of any systematic review is in the quality of the papers available for review. Clinical studies included in our review did not provide sample size and power calculations. Preclinical studies did not always use a classification system to identify stage of AVN of the FH. There were a limited number of comparative trials, and only two RCTs. We included all types of clinical studies, potentially introducing confounding and selection bias. We felt that inclusion of these studies would provide a more comprehensive review of the literature surrounding this topic. Furthermore, meta-analysis was not performed due to the limited number of comparative trials and variable methodology employed in the studies.
Competing interests
There are no competing interests for any author of this study.
Authors’ contributions
RL contributed to the design of the study, performed collection and assembly of data, analysis and interpretation of data and drafting and critical revision of the article. RG conceived and designed the study, drafted and critically revised the article, and gave final approval of the article. HE performed data collection and assembly and drafting of the article. SM performed data collection and assembly and drafting of the article. NM participated in study design and coordination, revised and gave final approval of the article. All authors read and approved the final manuscript.