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 . 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 .
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 . 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 . 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 .
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 . 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 . This may occur as a result of inadequate numbers of progenitor cells in the proximal femur of patients with AVN of the FH . It is thought that SC implanted into the necrotic region of the FH work to repopulate the low numbers of progenitor cells . 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 . However, the dose of SC used has been reported to impact disease outcome . 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 . Quality of transplanted cells affects their proliferative capacity . Prior to routine use of combined SC/CD therapy, defined standards of SC dose and quality, such as CD34+ or CFU counts , 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 . 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 . 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 . 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.