Jean-Philippe Hauzeur

Treatment of osteonecrosis of the femoral head with implantation of autologous bone-marrow cells. A pilot study.

BACKGROUND Aseptic nontraumatic osteonecrosis of the femoral head is a disorder that can lead to femoral head collapse and the need for total hip replacement. Since osteonecrosis may be a disease of mesenchymal cells or bone cells, the possibility has been raised that bone marrow containing osteogenic precursors implanted into a necrotic lesion of the femoral head may be of benefit in the treatment of this condition. For this reason, we studied the implantation of autologous bone-marrow mononuclear cells in a necrotic lesion of the femoral head to determine the effect on the clinical symptoms and the stage and volume of osteonecrosis. METHODS We studied thirteen patients (eighteen hips) with stage-I or II osteonecrosis of the femoral head, according to the system of the Association Research Circulation Osseous. The hips were allocated to a program of either core decompression (the control group) or core decompression and implantation of autologous bone-marrow mononuclear cells (the bone-marrow-graft group). Both patients and assessors were blind with respect to treatment-group assignment. The primary outcomes studied were safety, clinical symptoms, and disease progression. RESULTS After twenty-four months, there was a significant reduction in pain (p = 0.021) and in joint symptoms measured with the Lequesne index (p = 0.001) and the WOMAC index (p = 0.013) within the bone-marrow-graft group. At twenty-four months, five of the eight hips in the control group had deteriorated to stage III, whereas only one of the ten hips in the bone-marrow-graft group had progressed to this stage. Survival analysis showed a significant difference in the time to collapse between the two groups (p = 0.016). Implantation of bone-marrow mononuclear cells was associated with only minor side effects. CONCLUSIONS Implantation of autologous bone-marrow mononuclear cells appears to be a safe and effective treatment for early stages of osteonecrosis of the femoral head. Although the findings of this study are promising, their interpretation is limited because of the small number of patients and the short duration of follow-up. Further study is needed to confirm the results.

Treatment of Osteonecrosis of the Femoral Head with Implantation of Autologous Bone-Marrow Cells

BACKGROUND Aseptic nontraumatic osteonecrosis of the femoral head is a disorder that can lead to femoral head collapse and the need for total hip replacement. Since osteonecrosis may be a disease of mesenchymal cells or bone cells, the possibility has been raised that bone marrow containing osteogenic precursors implanted into a necrotic lesion of the femoral head may be of benefit in the treatment of this condition. For this reason, we studied the implantation of autologous bone-marrow mononuclear cells in a necrotic lesion of the femoral head to determine the effect on the clinical symptoms and the stage and volume of osteonecrosis. METHODS We studied thirteen patients (eighteen hips) with stage-I or II osteonecrosis of the femoral head, according to the system of the Association Research Circulation Osseous. The hips were allocated to a program of either core decompression (the control group) or core decompression and implantation of autologous bone-marrow mononuclear cells (the bone-marrow-graft group). Both patients and assessors were blind with respect to treatment-group assignment. The primary outcomes studied were safety, clinical symptoms, and disease progression. RESULTS After twenty-four months, there was a significant reduction in pain (p = 0.021) and in joint symptoms measured with the Lequesne index (p = 0.001) and the WOMAC index (p = 0.013) within the bone-marrow-graft group. At twenty-four months, five of the eight hips in the control group had deteriorated to stage III, whereas only one of the ten hips in the bone-marrow-graft group had progressed to this stage. Survival analysis showed a significant difference in the time to collapse between the two groups (p = 0.016). Implantation of bone-marrow mononuclear cells was associated with only minor side effects. CONCLUSIONS Implantation of autologous bone-marrow mononuclear cells appears to be a safe and effective treatment for early stages of osteonecrosis of the femoral head. Although the findings of this study are promising, their interpretation is limited because of the small number of patients and the short duration of follow-up. Further study is needed to confirm the results.

Autologous bone marrow cell implantation in the treatment of non-traumatic osteonecrosis of the femoral head: Five year follow-up of a prospective controlled study

OBJECTIVE To determine the efficacy of bone marrow cell implantation into the necrotic lesion of the femoral head on clinical symptoms and the progression of osteonecrosis of the femoral head in comparison with core decompression. METHODS We studied nineteen patients and twenty four hips with early stage osteonecrosis of the femoral head. The hips were allocated to either core decompression only or core decompression and implantation of bone marrow cells. Both patients and assessors were blind with respect to treatment group assignment. The primary outcomes were clinical symptoms and disease progression. RESULTS Bone marrow implantation afforded a significant reduction in pain and in joint symptoms and reduced the incidence of fractural stages. At 60 months, eight of the eleven hips in the control group had deteriorated to the fractural stage whereas only three of the thirteen hips in the bone marrow graft group had progressed to that stage. Survival analysis showed a significant difference in the time to failure between the two groups at 60 months. Patients had only minor side-effects after the treatments. CONCLUSIONS This long term follow-up study confirmed that implantation of autologous bone marrow cells in the necrotic lesion might be an effective treatment for patients with early stages of osteonecrosis of the femoral head.

Stem cell therapy for osteonecrosis of the femoral head

Aseptic non-traumatic osteonecrosis of the femoral head is a painful disorder of the hip that can lead to femoral head collapse and the need for total hip replacement. As osteonecrosis may be a disease of mesenchymal cells or bone cells, the possibility has been raised that bone marrow containing osteogenic precursors implanted into the necrotic lesion could be of benefit in this condition. Indeed, bone marrow contains adult stem cells, such as haematopoietic stem cells, mesenchymal stem cells and multipotent stem cells, that might have osteogenic properties. The efficacy of bone marrow implantation into the osteonecrotic zone was studied in two prospective trials. This treatment avoided the progression of the disease to the stage of the subchondral fracture (stage III) and reduced the need for total hip replacement. The mechanisms involved might include improved osteogenesis and angiogenesis. This new therapeutic approach should modify the treatment of early-stage osteonecrosis of the femoral head.

Discovery and biochemical characterisation of four novel biomarkers for osteoarthritis

Objective Knee osteoarthritis (OA) is a heterogeneous, complex joint pathology of unknown aetiology. Biomarkers have been widely used to investigate OA but currently available biomarkers lack specificity and sensitivity. Therefore, novel biomarkers are needed to better understand the pathophysiological processes of OA initiation and progression. Methods Surface enhanced laser desorption/ionisation-time of flight-mass spectrometry proteomic technique was used to analyse protein expression levels in 284 serum samples from patients with knee OA classified according to Kellgren and Lawrence (K&L) score (0–4). OA serum samples were also compared to serum samples provided by healthy individuals (negative control subjects; NC; n=36) and rheumatoid arthritis (RA) patients (n=25). Proteins that gave similar signal in all K&L groups of OA patients were ignored, whereas proteins with increased or decreased levels of expression were selected for further studies. Results Two proteins were found to be expressed at higher levels in sera of OA patients at all four K&L scores compared to NC and RA, and were identified as V65 vitronectin fragment and C3fpeptide. Of the two remaining proteins, one showed increased expression (unknown protein at m/z of 3762) and the other (identified as connective tissue-activating peptide III protein) was decreased in K&L scores >2 subsets compared to NC, RA and K&L scores 0 or 1 subsets. Conclusion The authors detected four unexpected biomarkers (V65 vitronectin fragment, C3f peptide, CTAP-III and m/z 3762 protein) that could be relevant in the pathophysiological process of OA as having significant correlation with parameters reflecting local inflammation and bone remodelling, as well as decrease in cartilage turnover.

Cellular-Based Therapy for Osteonecrosis

This review article describes bone remodeling in the context of osteonecrosis as a bone disease, the use of stem cells in bone and vascular diseases, and cellular therapy in osteonecrosis.

The apoptosis of osteoblasts and osteocytes in femoral head osteonecrosis: its specificity and its distribution

The pathogenesis of nontraumatic osteonecrosis (ON) remains unclear. Some studies have suggested that nontraumatic ON is attributed to increased osteocytic apoptosis. To test this hypothesis, a controlled study must compare the apoptosis of osteocytes and osteoblasts in cases of ON and osteoarthritis (OA). To assess either the localized or diffuse patterns of this increased osteocytic and osteoblastic apoptosis, we evaluated both the proximal and distal regions of necrotic areas. Femoral heads resected for total hip prosthesis were included for this study. Of these, 10 were ON cases—three were induced by corticosteroids, three by alcohol abuse, one resulted from trauma, one resulted from hyperlipemia, and two were idiopathic—10 were osteoarthritis cases, and 1 from a patient suffering from a subcapital fracture. The TUNEL reaction was used to detect the apoptosis in osteoblasts and osteocytes. A semi-quantitative evaluation was conducted, at both distal and proximal areas relative to the lesions, specifically in the area surrounding the necrotic region in the osteonecrosis cases, in the eburnated bone in the osteoarthritis cases, and in the subchondral bone fracture. The apoptosis of osteoblasts and osteocytes was statistically more frequent in the regions close to the necrotic areas in the ON group. No difference was found in the unpaired areas. In the ON group, no difference was found in terms of the etiological factors. During ON, the apoptosis of osteocytes and osteoblasts is increased proximally to the necrotic regions in the patients presenting with osteoarthritis and subcapital fractures. This increase was found not only in the corticosteroid-induced ON cases but also in the idiopathic and alcohol abuse- and trauma-induced ON cases.

Phases 1–3 Clinical Trials Using Adult Stem Cells in Osteonecrosis and Nonunion Fractures

Nonunion fractures and aseptic bone necrosis are two pathological conditions having some impairment of the cellular part of the repair: a reduction of MSC and of the osteoblastic activation. Both are good candidates for cell-based therapies using stem cells. We made a review of the published human trials. Only autologous bone marrow aspirate implantation was until now used. In Nonunion, a direct injection—15 to 150 ml—was made in 4 case series studies. In another, the bone marrow aspirate was concentrated before injection. The results were good. In bone necrosis, only one level 1 study was published. The results at 24 months were positive in terms of reduction of the necrosis and appearance of collapse. In 3 case series studies, a treatment with concentrated bone marrow aspirates was deemed useful with good results in 76 to 96%. These results are interesting but need confirmation by controlled studies.

Stress fracture of the sacrum

The patient, a 40-year-old man who was running 80 km weekly, complained of the sudden onset of pain in the right lumbosacral area during his training. The pain did not disappear, despite a dramatic reduction in his training. Physical examination was normal except for pain on movement of the right hip. A technetium methylene diphosphonate bone scan disclosed increased activity in the upper portion of the right sacral wing. Conventional radiographs (Fig. 1) revealed a vague, obliquely oriented area of increased density on the right side of the first sacral segment with interruption of the anterior margin of the foramen and surrounding a radiolucent line inferiorly. No other radiologic abnormality was identified in the pelvis, hips, or lumbar spine. A pelvic CT

Treating osteonecrosis with autologous bone marrow cells

Osteonecrosis is a devastating disease that primarily affects weight-bearing joints. The hip is the most commonly affected joint. Although osteonecrosis of the femoral head can affect patients of any age group, it typically presents in young patients between the ages of 20 and 40. The evolution of osteonecrosis is towards femoral head collapse, osteoarthritis and finally total hip replacement. Osteonecrosis is believed to be a multifactorial disease that is associated in some cases with both genetic predilection and exposure to certain risk factors. These risks factors include corticosteroid use, alcohol intake, smoking and various chronic diseases such as renal disease, haematological disease, inflammatory bowel disease, post-organ transplantation, systemic lupus erythematosus and human immunodeficiency virus. However, in Caucasians, corticosteroids and alcohol abuse are among the most widely recognized risk factors for osteonecrosis. In some cases, osteonecrosis of the femoral head has also been associated with certain genetic polymorphisms such as alcoholmetabolizing enzymes and the drug-transport protein Pglycoprotein. Liu et al. also identified three families with an autosomal dominant inheritance of osteonecrosis of the femoral head and mapped the chromosomal position of the collagen type-II gene (COL2A1 gene) mutation [1]. The importance of those findings is that genetic screening of families with osteonecrosis could be used to identify carriers before the onset of clinical symptoms and screening with magnetic resonance imaging (MRI) could enable an early diagnosis and the initiation of measures that could delay disease progression. Magnetic resonance imaging is important in the diagnosis of hip osteonecrosis as well as in predicting the outcome. Standard radiographs are commonly used to stage the progression of the disease. The factors that affect the progression of this disease are still not fully understood but lesion size, stage of disease (femoral head collapse), time from the diagnosis and etiological factors have been shown to be predictive of the clinical outcome. The most important factor in predicting the outcome of osteonecrosis is the size of the necrotic lesion [2]. The lesion size can be estimated radiographically when evident and by MRI during early stages of the disease. Different methods have been assessed radiographically and by MRI to measure the amount of femoral head involvement by osteonecrosis (calculation of necrotic angle, of necrotic index, estimation of percent of involvement and exact volumetric analysis). They can all be used with confidence as they are highly reliable and reproductible. There continues to be a lack of consensus concerning the pathogenesis and treatment of the disease despite recent outstanding studies and reviews. Different mechanisms leading to ischemia have been postulated including fat emboli, microvascular tamponade of the blood vessels of the femoral head by marrow fat, retrograde embolization of the marrow fat and intravascular coagulation. However, none of those mechanisms explored the necrotic lesion as a primary bone disease. Indeed, osteonecrosis is characterized by apoptosis of osteocytes and cancellous bone lining cells in the necrotic lesion and also at some distance from the lesion, in the proximal femur [3]. The replicative capacities of osteoblastic cells obtained from the intertrochanteric area V. Gangji (*) : J.-P. Hauzeur Rheumatology and Physical Medicine Department, Erasme Hospital, Université Libre de Bruxelles, 808 Route de Lennik, 1070 Bruxelles, Belgium e-mail: valerie.gangji@erasme.ulb.ac.be