Cell-Based Therapies for Osteonecrosis of the Femoral Head - Core

REVIEW

Cell-Based Therapies for Osteonecrosis of the Femoral Head Kevin B. Jones,1,3 Tara Seshadri,2,3 Roselynn Krantz,2 Armand Keating,2,3 Peter C. Ferguson1,3 Osteonecrosis of the femoral head is a disabling condition and a known complication of hematopoietic cell transplants (HCT). It is characterized by empty lacunae in the osseous matrix and necrotic marrow elements. The most important risk factor in HCT recipients is steroid exposure, frequently in the context of graft-versus-host disease. Current treatment is surgical, and involves decompression of the affected area and the use of bone grafts or hip arthroplasty. Cellular-based therapies are now under investigation, and can be used in addition to, or instead of, invasive surgery. This review presents an overview of osteonecrosis with particular emphasis on HCT recipients and introduces the role of cell therapy, especially with mesenchymal stromal cells, as a promising new treatment. Biol Blood Marrow Transplant 14: 1081-1087 (2008) Ó 2008 American Society for Blood and Marrow Transplantation

KEY WORDS: Osteonecrosis, Mesenchymal stem cell, Femoral head

INTRODUCTION Osteonecrosis of the femoral head is a common disorder, with 15,000-20,000 new cases estimated to occur each year in the United States. In North America, osteonecrosis leads to approximately 5% to 18% percent of the more than 500,000 total hip arthoplasties performed annually. In many Asian countries, where there is a greater prevalence, this disorder accounts for a majority of hip arthoplasties performed each year. With progression of the disease to femoral head collapse and symptomatic hip arthritis, a total joint arthroplasty is often required, but the percentage of good to excellent results for hip replacement is not as high in patients with osteonecrosis as it is in other patient populations. There are characteristic pathologic features of osteonecrosis in this anatomic location. Nonetheless, the pathophysiology remains poorly understood. Although a number of different etiologies have been identified, the clinical presentation results from elements of the final common pathway of ischemia, oste-

From the 1Division of Orthopedics, Department of Surgery, Mount Sinai Hospital, Toronto, Ontario; 2Cell Therapy Program, Princess Margaret Hospital, Toronto, Canada; and 3University of Toronto, Toronto, Canada Correspondence and reprint requests: Kevin B. Jones, MD, Mt. Sinai Hospital, 600 University Avenue, Suite 476G, Toronto, Ontario, Canada (e-mail: [email protected]). Received June 20, 2008; accepted June 23, 2008 1083-8791/08/1410-0001$34.00/0 doi:10.1016/j.bbmt.2008.06.017

ocyte necrosis, inadequate repair, loss of structural integrity of the subchondral trabecuale, and subchondral collapse. A number of risk factors are well characterized, with steroid exposure most prominent among them. However, some patients with osteonecrosis of the femoral head have no appreciable risk factors. Osteonecrosis primarily afflicts individuals in their third, fourth, and fifth decades, who then usually require multiple surgical procedures during their lifetime. Identification of the most effective, population-specific, and joint-conserving procedures are essential in the reduction of morbidity and burden of illness. Definition As a pathologic entity [1,2], osteonecrosis is defined by the presence of osseous matrix bearing empty lacunae, the spaces normally populated by living osteocytes. Also necrotic are the marrow elements that would otherwise fill the interstices of the trabecular bone. In the femoral head specifically, this region of necrotic, acellular bone tissue, called the sequestrum, is surrounded by reparative tissues, including a sweeping front of revascularization and bone formation. Unfortunately, this healing process, named creeping substitution [3], is rarely capable of returning structural stability to the femoral head prior to progression to mechanical failure in the form of subchondral collapse [4]. Clinically, patients with osteonecrosis of the femoral head first present for medical attention with hip pain. Radiographs reveal few or no findings early in 1081

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the course of disease, but magnetic resonance imaging has made earlier diagnosis possible. A patient’s disease is characterized by imaging findings that display both the extent of involved tissue and the stage of structural collapse [5,6]. Imaging systems have been developed to facilitate and standardize description of the progression of the disorder. Treatments are therefore tailored to the stage of disease and vary widely. Without intervention, most patients eventually have sufficient progression of disease [4] that hip arthroplasty becomes the only definitive option. Because many young patients are affected and even the good outcomes of such arthroplasties are insufficiently durable, much attention is focused on developing effective treatments of the early stages of disease to prevent femoral head collapse, which invariably leads to secondary arthritis. Nonetheless, no current method of treatment is consistently effective, and each has drawbacks, driving a search for improved methods. Associated Risk Factors The 2 most common exposures associated with the development of osteonecrosis are use of corticosteroids [7] and excessive ingestion of alcohol [8]. The term avascular necrosis—falling out of favor recently, but used for decades to describe the condition—relates more directly to other known risk factors, each associated with varied intravascular or extravascular means of blood supply disruption to the femoral head. These include traumatic hip dislocation, displaced femoral neck fracture, vasculitis, Caisson’s disease, and sickle cell anemia. Infection with and treatments for the human immunodeficiency virus, chronic renal disease, and certain chemotherapeutic regimens are also considered risk factors. For some patients, no specific risk factor is identified. The complexities inherent to an understanding of the pathophysiology of osteonecrosis of the femoral head are well illustrated in the study of the high incidence of osteonecrosis following hematopoietic cell transplants (HCT). Although this association has been well recognized for 20 years, it is far from being well understood [9]. The prevalence appears significantly higher after allogeneic HCT than autologous HCT [10]. Cumulative incidence of this complication generally ranges from 5% to 20% at 5 to 15 years after HCT [11-14], with the mean time from HCT to osteonecrosis development being 12 to 15 months [11,12,15]. An obvious focus in understanding this setting for osteonecrosis of the femoral head has been the use of corticosteroids for the treatment of related acute or chronic graft-versus-host disease (aGVHD ,cGVHD). Although corticosteroid use in this circumstance has consistently been demonstrated to be an important risk factor for osteonecrosis formation [13,16-18],

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the relative importance of corticosteroid use versus the inflammatory changes in the microvasculaure from the GVHD itself are difficult to tease out. Most of the data available from the literature are retrospective and rarely include corticosteroid dosing. A large retrospective study by Socie et al. [13] analyzed risk factors for the development of osteonecrosis following allogeneic hematopoietic stem cell transplant in 4388 patients. They reported odds ratios of 3.73 and 3.52 for aGVHD and cGVHD, respectively. Severity of GVHD also correlated with a higher frequency of osteonecrosis. Unfortunately, the details of corticosteroid dosing were not analyzed, leaving as many questions as answers. In a smaller, but prospective study, Schulte et al. [14] followed 255 patients for a period of 4 years after allogeneic HCT for various hematologic diseases. Chronic GVHD was associated with severe osteonecrosis. However, steroid intake appeared to correlate better and remained significantly predictive of the development of osteonecrosis in the multivariate analysis. Another prospective study on 553 patients with multiple myeloma undergoing autologous HCT found a direct relationship between cumulative dexamethasone exposure and osteonecrosis incidence [19]. Subgroup risk factors of age and gender for the development of osteonecrosis following HCT have been inconsistently reported in the literature. Some studies reported that younger age at transplant appeared to increase the risk [14,20], whereas others found older age at transplant [18,21] and older age per se were more significant [11,13]. An early study initially demonstrated that male gender was associated with an increased the risk of osteonecrosis [12]; however, later studies have demonstrated a higher incidence in females [14] and others have not demonstrated any significance of gender at all [11,22]. The impact of the HCT-prompting underlying disease on the development of osteonecrosis has also been explored. One study reported that the incidence of osteonecrosis was significantly higher in patients who underwent allogeneic HCT for diseases other than chronic myeloid leukemia (CML) [14]. Here, no cases of severe hip osteonecrosis occurred in the 152 patients with CML versus a 4-year cumulative incidence of 20% in patients with other hematologic diseases (P \ .0001). In contrast, other investigators have demonstrated relatively similar incidences of osteonecrosis in their CML and acute myeloid leukemia (AML) patients at approximately 10% and 7%, respectively [17]. Another long-term follow-up study of CML patients undergoing allogeneic HCT found a 12% incidence of osteonecrosis at 15 years postHCT with those patients experiencing cGVHD demonstrating increased risk [23]. As with age and gender, underlying disease as an independent risk factor is far from sorted out.


Finally, total body irradiation (TBI) may contribute to the development of osteonecrosis of the femoral head. In an analysis of 4 studies that compared the conditioning regimens busulfan-cyclophosphamide and TBI-cyclophosphamide in patients with AML and CML [17], patients with CML who received TBI-based conditioning had a higher incidence of osteonecrosis (10%) compared to those who received bulsulfan-cyclophosphamide (3%). However, the contribution of TBI to the development of osteonecrosis was not significant in the multivariate analysis. Further, no significant difference was noted with the AML cohort. Two other studies have demonstrated a higher risk of osteonecrosis in TBI recipients on univariate analysis [13,24], but again, significance was not reached after adjusting for confounding factors [13]. As an illustration of the difficulties intrinsic to understanding osteonecrosis of the femoral head in general, the study of its development following HCT has raised, but not settled the potential contributions of GVHD, corticosteroid treatment for GVHD, underlying hematologic malignancy or other disease, TBI, age, and gender. As is the case with other settings of osteonecrosis, the use of corticosteroids following HCT is the best documented risk factor. Even if risk factor associations are difficult, however, their study is far ahead of the study of pathogenesis of osteonecrosis of the femoral head. Theories on Pathogenesis Although the death of osteocytes and marrow elements in a region of limited blood supply can be readily explained by traumatic disruption of all vascular routes in and out of the region [25], understanding how exposure to steroids or excessive ethanol leads to an identical pathology has been less forthcoming. Decades of research have led to the development of a number of theories, including venous occlusion [25], vessel wall injury [26], fat embolism [27], microfracture from trabecular insufficiency, intraosseous hypertension [28], intraosseous hemorrhage [29], vasculitis [30], and intravascular coagulation [31], none of which has been proven in more than a minority of cases or modeled to effectively recapitulate the pathology in an animal model. A major challenge to understanding osteonecrosis of the femoral head is the variability in its development. Even complete traumatic disruption of femoral head perfusion does not consistently lead to osteonecrosis. There is certainly a time element that figures prominently in the course of the disease, where healing of an insulted femoral head races mechanical failure. Variation in the time course of healing in different patients may generate the recognized clinical entity more than the initial insult itself. As noted above, the 2 most common risk factors for osteonecrosis of the femoral

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head are systemic exposures that generally alter musculoskeletal healing potential. Further, local (proximal femur away from the sequestrum) [32] and even regional (ilium) [33] deficits in the osteogenic potential of available mesenchymal cell populations have been demonstrated in patients with osteonecrosis from varied etiologies. These suggest that a global or regional disablement of healing potential may yield the conditions that generate clinically apparent osteonecrosis. This is corroborated by the demonstration that exposure to corticosteroids, which increases an individual’s risk for osteonecrosis of the femoral head, also shunts mesenchymal progenitor cells toward adipogenesis and away from osteogenesis [34,35].

Traditional Treatment Paradigms Total hip arthroplasty remains the only definitive treatment of osteonecrosis of the femoral head, in that the presumably diseased tissues are completely resected, prior to reconstruction with artificial implants. Although the bulk of disease is irrevocably removed, the durability of the reconstructive option is usually insufficient for the young population affected by osteonecrosis. Further, there is the suspicion that long-term results of total hip arthroplasty in the specific setting of osteonecrosis of the femoral head are compromised by more than just the elevated longevity and activity levels of the young patients affected [36,37]. It is suspected that other, yet unexplored aspects of the biology of osteonecrosis may affect the interface of the surrounding bones with the implants. A regional or even global deficit in osteogenic reserves is suggested. For these reasons, arthroplasty is an undesirable last resort in most patients with osteonecrosis. Most other available treatments aim at postponing, if not preventing the structural collapse of the femoral head, which nearly always results in the need for arthroplasty. Pharmacotherapy A number of drugs have been suggested for use in treating osteonecrosis, but have never gained the momentum or the evidence required for widespread use. These would include certain antihypertensive medications, lipid lowering agents, and anticoagulants. More recently proposed and definitely gaining momentum has been the use of bisphonates [38-41]. These ignore the pathophysiology of the disease process, but directly tackle the disabling result of that pathophysiology—mechanical failure of the osteonecrotic femoral head. Although bisphosphonates show promise as effective short-term deferment pharmacotherapies, the duration of effectiveness against collapse and the long-term risks of the use of bisphosphonates in the young adult population have not been fully

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explored. For the present, these are at best considered as temporizing treatments only. Core decompression The most commonly implemented treatment for osteonecrosis of the femoral head is core decompression. Originally described by Ficat and Arlet [42], opening the osteonecrotic zone of the femoral head with trephines, drills, or reamers introduced laterally via the trochanter and femoral neck is readily performed by most orthopedic surgeons and carries few serious risks beyond progression of the disease itself. A systematic review [4] of 24 studies including 1206 patients noted clinical success in 63% of precollapse patients and 23% progression to total hip arthoplasty by a mean follow-up of 30 months. As the decompression naturally leaves a structural defect, many methods of filling the trephine’s track have been utilized, including varied bone grafts, bone graft substitutes, and even metallic implants [43]. Bone grafting The original idea behind the use of bone grafting after drilling of osteonecrosis was to reconstruct the structural integrity of the bone. Stuctural grafts were originally made popular by Phemister [44]. Although early results of these techniques seemed promising initially [45], longer follow-up showed only 25% success at a mean of 16 years [46]. Nonetheless, structural bone grafts applied via a number of anatomic approaches continue to be utilized by some treating surgeons [47-49]. In the middle of the 1970s, it began to be proposed that the biologic activity of bone grafts might be more critical than the structural stability alone [50]. High failure rates led to the consideration of varied forms of vascularized bone tissue transfers. The technique that reported the strongest results was the use of a free, vascularized fibular autograft [51]. Unfortunately, this technique is arduous, expensive, and not widely reproducible at many medical centers. Cell-Based Therapies A convergence of 3 different perspectives on the treatment of osteonecrosis has resulted in exploration of cell-based therapies. First, patient and surgeondriven emphasis on minimizing the invasiveness of surgical interventions has led many to question both the complexity and donor site morbidity of vascularized free fibular transfers and the pain associated with iliac crest-derived autografts. Second, the unassailable recognition that the time course to healing may critically differentiate between an ultimately preserved and an ultimately collapsed femoral head has emphasized the importance of potential methods to enable the healing process. Finally, the contribution of a compro-


mised healing capacity as a pathologic feature of osteonecrosis has been recognized, urging the need to introduce healing potential exogenously. Recognizing the potential role of a mesenchymal cell deficit in the evolution of the disease, Gangji et al. [52] undertook a small prospective cohort study to assess the safety and efficacy of the transplant of autologous bone marrow mononuclear cells into the necrotic lesion of the femoral head in patients with early stage (I and II) osteonecrosis. Overall significant decreases in level of pain and joint symptoms and a significant reduction in the ratio of volume of the necrotic lesion to volume of femoral head where observed. Five of the 8 control group members deteriorated to stage III disease, whereas only 1 of the 10 transplanted patients progressed to this stage. No significant treatment-related adverse effects were noted in either group. As the use of cellular grafts simply arose as an extension of bone grafting, the bulk of experimentation has been without preclinical background. This is partly because of the paucity of good animal models of the full process of osteonecrosis and subsequent collapse. The use of an iliac crest bone marrow aspirate rather than a surgically obtained iliac crest bone graft was initially proposed in 1990 as an appropriate, biologically active filler for the defect left after decompression [53]. A few reports have followed, including results from 2 formal series [52-58]. Hernigou and Beaujean [54] reported .5-year follow-up results from 116 patients with 189 affected hips treated by core decompression and implantation of the mononuclear cell component from centrifugation of aspirated iliac crest bone marrow. Only 9 of 145 precollapse patients went on to need hip arthoplasty. Twenty-five of 44 collapsed femoral heads needed arthoplasty by the end of follow-up. Further, a dose-response correlation was noted between the clinical success rate and the separately measured concentration of fibroblast colony forming units (F-CFU) implanted. Of note, the number of F-CFU obtained from patients who developed osteonecrosis secondary to alcohol or corticosteroid use was lower than the number of F-CFU found in patients who had a different underlying etiology. This was interpreted as evidence that corticosteroids and alcohol may be specifically toxic to these progenitor cells. Another article [58] reported on 3 patients treated with core decompression, free vascularized fibula, and autologous mesenchymal stem cells cultured in beta-tricalcium phosphate ceramic. Few conclusions can be drawn from the small number in this latter study, but it demonstrates that new techniques continue to be attempted. Preclinical models for testing are somewhat scarce, as only 2 have been described that proceed to full collapse of the femoral head [59-61]. One of these has been tested with human bone morphogenic protein 2 gene-transduced bone marrow-derived mesenchymal


stem cells embedded in a beta-tricalcium phosphate ceramic. Results were promising, in that collapse could be thwarted and healing complete.

CONCLUSIONS Although the etiology of osteonecrosis of the femoral head remains elusive, associated local deficits in the regenerative potential of autologous stem cells have been noted. This has long raised awareness of the need to alter the biologic capacity for repair. Although this has traditionally been addressed with vascularized and nonvascularized bone grafts, the complexities, complications, and failure rates of these procedures drive the continued search for less invasive, more effective treatments. The use of bone marrowderived mesenchymal stromal cells (MSCs) as an adjunct to core decompression has shown promising results in 1 large series, and statistically significant improvements in outcomes in a small pilot randomized control trial. On theoretical grounds alone, there are several compelling reasons to consider the MSC population [62]—whether derived from the bone marrow or from other sources—as particularly suitable for the regeneration of osteonecrotic bone. First, in vitro as well as in vivo data suggest that MSCs are capable of undergoing osteogenic differentiation and mediating bone mineralization [63,64]. Second, their role in improving the hemodynamic function of injured myocardium in animal models has been attributed to the elaboration of paracrine factors such as vascular endothelial growth factor that lead to neovascularization [65]. Additionally, it is possible that the regenerative potential of MSCs is influenced by remodelling of the extracellular matrix [66], a conceivably important factor in reversing the pathologic processes that initiate osteonecrosis. Nonetheless, autologous bone marrow-derived MSCs in patients with osteonecrosis of the femoral head show decreased regenerative potential, perhaps as a result of exposure to the same (bone marrow modifying/toxic) pharmacologic agents (ie, steroids and alcohol) or as a result of risk-elevating comorbid illnesses. Allogeneic MSCs from normal donors would be expected to exert superior regenerative properties, thereby overcoming the limitations of autologous cells. Moreover, there is accumulating evidence that MSCs are nonimmunogenic and do not require HLA matching with the recipient to exert an effect [63]. Sources of such cells are plentiful and are not restricted to the bone marrow but include adipose tissue and the umbilical cord [67]. Given the morbidity associated with osteonecrosis of the femoral head, early phase studies with MSCs should be encouraged.


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ACKNOWLEDGMENTS A.K. holds the Gloria and Seymour Epstein Chair in Cell Therapy and Transplantation at University health Network and the University of Toronto. T.S. thanks the Haematology Sociey of Australia and New Zealand for financial assistance of her fellowship.

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