The pathophysiological basis of alterations in trabecular bone of patients with osteonecrosis of the femoral head (ONFH) remains unclear. ONFH has classically been considered a vascular disease with secondary changes in the subchondral bone. However, there is increasing evidence suggesting that ONFH could be a bone disease, since alterations in the functionality of bone tissue distant from the necrotic lesion have been observed. We comparatively studied the transcriptomic profile of trabecular bone obtained from the intertrochanteric region of patients with ONFH without an obvious aetiological factor, and patients with osteoarthritis (OA) undergoing total hip replacement in our Institution. To explore the biological processes that could be affected by ONFH, we compared the transcriptomic profile of trabecular bone from the intertrochanteric region and the femoral head of patients affected by this condition. Differential gene expression was studied using an Affymetrix microarray platform. Transcriptome analysis showed a differential signature in trabecular bone from the intertrochanteric region between patients with ONFH and those with OA. The gene ontology analyses of the genes overexpressed in bone tissue of patients with ONFH revealed a range of enriched biological processes related to cell adhesion and migration and angiogenesis. In contrast, most downregulated transcripts were involved in cell division. Trabecular bone in the intertrochanteric region and in the femoral head also exhibited a differential expression profile. Among the genes differentially expressed, we highlighted those related with cytokine production and immune response. This study identified a set of differently expressed genes in trabecular bone of patients with idiopathic ONFH, which might underlie the pathophysiology of this condition. Acknowledgements: This work was supported by grants PI18/00643 and PI22/00939 from ISCIII-FEDER, Ministerio de Ciencia, Innovación y Universidades (MICINN)-AES

Introduction. The most frequent diagnosis in young adults undergoing total hip arthroplasty (THA) is osteonecrosis of the femoral head (ONFH), an evolving and disabling condition with an increasing prevalence worldwide. Treatment of ONFH remains a challenge mainly because of a lack of understanding of the disease's pathophysiological basis. This study investigated the biological processes that could be affected by ONFH by comparing the microstructure, histological characteristics and transcriptomic profile of trabecular bone from the femoral head (FH) and the intertrochanteric region (IT) of patients suffering from this condition. Method. A total of 18 patients with idiopathic ONFH undergoing THA in our institution were included. Trabecular bone explants were taken intraoperatively from the FH and the IT of patients. Bone microstructure was examined by micro-computed tomography (micro-CT). After bone sectioning, histological features were studied by hematoxylin and eosin staining. Differential gene expression was investigated using a microarray platform. Result. Micro-CT imaging showed higher trabecular separation and lower trabecular thickness and bone volume in trabecular bone from the FH than from the IT. Histological staining revealed that the number of osteoblasts on the bone surface and the percentage of empty lacunae were higher in trabecular bone from the FH. Transcriptome analysis identified a differential signature in trabecular bone from the FH compared to the IT. The gene ontology analyses of the genes overexpressed in trabecular bone from the FH revealed a range of enriched biological processes related to cell division and immune response. In contrast, most downregulated transcripts were involved in bone formation. Conclusion. This study identified changes in the microarchitecture, histological features and transcriptomic signature of trabecular bone from the FH of patients with idiopathic ONFH, which might underlie the pathophysiology of this condition. This work was supported by PI22/00939 grant from ISCIII-FEDER-MICINN-AES and Luis Alvarez grant from IdiPAZ

Introduction. For many years, minimally invasive joint-preserving regenerative therapy has been desired for the early stages of osteonecrosis of the femoral head (ONFH). In an animal study using adult rabbits, we reported that a single local injection of rhFGF-2-impregnated gelatin hydrogel, which has superior slow-release characteristics, suppresses the progression of femoral head necrosis. The purpose of this study was to evaluate the safety and clinical outcomes of a single local administration of rhFGF-2-impregnated gelatin hydrogel for the precollapse stage of ONFH. Patients and Methods: Ten patients with femoral heads up to precollapse stage 2 underwent a single local administration of 800-µg rhFGF-2-impregnated gelatin hydrogel and were followed up for two years. The eligibility criteria were age between 20 and 80 years and presence of ONFH at precollapse stage 1 or 2 according to the classification system for ONFH developed by the Japanese Investigation Committee of Health and Welfare. Primary outcomes included adverse events and complications. Secondary outcomes included changes in Harris Hip Scores (HHS), visual analog scale pain scores (VAS), the University of California, Los Angeles (UCLA) activity rating scores, radiological changes as determined via radiographs, computed tomography (CT) scans, and magnetic resonance imaging (MRI) of the hip joint. Results: We included five men (five hips) and five women (five hips), with a mean age of 39.8 years (range: 29–53 years) at the time of surgery. Eight patients had bilateral ONFH, three had already undergone THA on the contralateral side. Eight patients were receiving treatment with corticosteroid therapy, and two patients overused alcohol. Stage 1 and 2 disease was present in one and nine patients, respectively. One patient each had type A, type B, and type C1 disease, whereas seven patients had a type C2 lesion. All Adverse events were recovered without problem. The surgery was performed with a minimally invasive technique based core decompression (1 cm of skin incision), and walking was allowed from the day after surgery. Mean clinical scores improved significantly after three year compared with before surgery (before vs. after: VAS for pain, 21.2 vs. 5.3 mm; UCLA activity score 5.5 vs. 6.6; HHS, 81.0 vs. 98.4 points, respectively). There was only one case of femoral head collapse, and it had the greatest necrosis volume fraction and was considered to be in the early collapse stage at the time of operation. The other nine cases did not involve ONFH stage progression, and collapse was prevented. CT images and recent MRI postoperatively confirmed bone regeneration and reduction of the necrotic area. Conclusion: Clinical application of rhFGF-2-impregnated gelatin hydrogel for patients with precollapse stage of ONFH was feasible and safe. Our research is ongoing, further phase II multiple center study has been started in January 2016

Introduction. The objective of this study was to verify the long-term outcome of transtrochanteric anterior rotational osteotomy (ARO) for osteonecrosis of the femoral head (ONFH) in young patients with systemic lupus erythematosus (SLE). Methods. Consecutive series of 21 symptomatic ONFH patients with SLE (33 hips), aged 20 to 40 years, underwent ARO between 1980 and 1988. We reviewed the cases of 16 patients (25 hips), which represents a 76% rate of follow-up. Patients included 4 men and 12 women who had a mean age of 29 years at the time of surgery. A Kaplan-Meier curve was used for the survivorship analysis of ARO. Patients with surviving hips were evaluated by the modified Oxford hip score and the Medical Outcomes Study Short Form 36 (SF-36). Results. Twelve hips in 8 patients survived at the final follow-up. The average length of surviving was 25 years (range, 20 to 27 years). Three patients (6 hips) had died of unrelated causes without any conversion at the mean time of 9 years after ARO. Based on Kaplan-Meier analysis with the end point defined as any conversion, the survival rate at 25 years was 73.7% (95% confidence interval, 53.9 to 93.5%). Based on the classification of the modified Oxford hip score, 5 hips were classified as excellent, 2 hips were good, and the remaining 5 hips were fair. The average SF-36 physical component summary score was 34 points and the average mental component summary score was 46 points. The physical component summary scores of 3 patients (53.0, 56.6, 57.1) exceeded the level of the Japanese population norm. Conclusion. In ONFH patients with SLE, ARO achieved a 73.7% survival rate at 25 years

Introduction. The purpose of this study was to evaluate the outcome of vascularized iliac bone grafting for idiopathic osteonecrosis of the femoral head. Methods. We reviewed the clinical and radiological results of 35 operations performed on 29 patients who had osteonecrosis of the femoral head (ONFH) in which a pedicle iliac bone grafting was performed for minimum follow-up of 10 years. The average age was 35 years (range, 17 to 62 years). According to the Japanese Orthopaedic Association classification for ONFH, there were 28 stage 2, 7 stage 3-A, 17 type C-1 hips, and 18 type C-2 hips. After a bone tunnel of 1.5 × 5 cm was made in the anterior aspect of the femoral head and curettage of necrotic lesion was performed, the pedicle bone with the deep circumflex iliac artery (DCIA) was inserted into the anterolateral portion of the femoral head. The average follow-up period was 13 years and 6 months. Weight bearing was not allowed for 2 months after the operation. Survival rate of the femoral head was calculated by Kaplan-Meier methods, and collapse of the femoral head and configuration of the femoral head was investigated at final follow-up. Results. Collapse of the femoral head occurred in 19 hip joints of 35 studied. Although only 16 of 28 stage 2 hips showed collapse, all 7 stage 3 hips collapsed. Four of 17 hips (24%) showed collapse in patients with type C-1 necrosis, whereas, 15 of 18 hips (83%) developed collapse in patients with type C-2 necrosis. When the bone graft was inserted in the anterolateral portion of the femoral head, the incidence of collapse was reduced. In patients without collapse for more than 12 years, osteoarthritic change was evident in 5 hips between 12 to 19 years after operation. Conclusion. In this study, we found that collapse of the femoral head occurred or progressed in almost half of our patients, and these findings allowed us to clarify the operative indications for DCIA pedicle bone graft. In patients with stage 3, DCIA pedicle bone graft could not prevent collapse of the femoral head. While 13 of 17 hips with type C-1 were prevented from collapse, only 3 of 18 with type C-2 did not show collapse. These results indicate that DCIA bone graft may be indicated for stage 2, type C-1 necrosis. However, technical demands of this surgery tend to make it a less routine application for the treatment of ONFH

Introduction. The crescent sign is thought to be an early indicator of collapse in osteonecrosis of the femoral head. However, the formation mechanism of the crescent sign is still not quite clear. The purpose of this study was to utilize the two-dimensional finite element model analysis (FEA) technique to analyze mechanical function of different structures and intraosseous fluid in the femoral head under the stress of physiological loading. We wished to answer the following question: which structure or structures' failure are the main causes of collapse in osteonecrosis of the femoral head (ONFH)?. Methods. Based on two femoral head specimens obtained during THA (one with osteonecrosis of the femoral head with crescent sign formation and the other with most of the cancellous bone eroded by tumor cells without collapse), three groups of ten models were designed. Group A were standard femoral heads composed of subchondral plate, cancellous bone, intraosseous fluid, and cortical bone with 50 mm in diameter, Group B included ONFH, and Group C was based on a tumor-eroded femoral head. Previously reported mechanical property parameters were used in the FEA calculation. The strain and Von Mieses stress mechanics parameters of fifteen points (with the same coordinates) in the junction between subchondral plate and cancellous bone were harvested and compared. Results. In the model, Group B3 (around the fissure region), had strains 12 times and Von Mieses' stresses 4.5 times higher than the values in same region of Group A1. Strain and Von Mieses stresses were concentrated in the fissure region and in the junction of the subchondral plate and the cancellous bone of the necrotic region. Conclusion. All three; the subchondral plate, cancellous bone, and intraosseous fluid, together played an important role for the femoral head to bear physiological loads. It is the fissure in the subchondral plate caused by the resorption that; 1) provides a channel for the intraosseous fluid to outflow and makes the necrotic region in both the subchondral plate and the cancellous bone lose mechanical support from the intraosseous fluid, and 2) destroys the function of the subchondral plate as a thin shell structure, making the stress and strain concentrate in the junction of the subchondral plate and the cancellous bone of the necrotic region. Concentrated stress leads to fracture of the junction between the subchondral plate and the cancellous bone and the formation of a crescent sign

Introduction. The treatment of osteonecrosis of the femoral head (ONFH) in young and active patients remains a challenge. The purpose of this study was to determine and compare the clinical and radiographic results of the two different hip resurfacing systems; hemi-resurfacing and metal-on-metal total hip resurfacing in patients with ONFH. Methods. This study was a retrospective review of 20 patients with 30 hips who had ONFH and underwent hemi-resurfacing or total hip resurfacing between November 2002 and February 2006. We mainly performed hemi-resurfacing for early stage ONFH, and total hip resurfacing for advanced stages. Fifteen hips in 11 patients had a hemi-resurfacing component (Conserve, Wright Medical Co) with a mean age at operation of 50 years and an average follow-up of 5.5 years. Fifteen hips in 10 patients had a metal-on-metal total hip resurfacing component (Birmingham hip resurfacing, Smith & Nephew Co.) with a mean age at operation of 40 years and an average follow-up years. Results. The average postoperative Japanese Orthopaedic Association (JOA) hip scores were 86 points in hemi-resurfacing and 96 points in total hip resurfacing. The difference of pain score was a main factor to explain the difference of total JOA hip score in the two groups. Both implants were radiographically stable, but radiolucent lines around the metaphyseal stem were more frequent in total hip resurfacing. In hemi-resurfacing patients, ten of 15 hips had groin pain or groin discomfort and three hips were revised to total hip arthroplasties (THA) because of femoral neck fracture, acetabular protrusio, and osteoarthritic changes, respectively. In total hip resurfacing patients, there were no revisions and no groin pain observed. Conclusion. In the prosthetic treatment of young active patients with ONFH, it is theoretically desirable to choose an implant with a conservative design in anticipation of the future revision surgery. Hemi-resurfacing hip arthroplasty is the most conservative implant for the treatment of ONFH. However, the results of hemi-resurfacing in this study have been disappointing due to high revision rates and insufficient pain relief despite of the good implant stability. However, the pain relief and implant survivorship after total hip resurfacing were superior to the results of hemi-resurfacing, although the usages of the total hip resurfacing were for more advanced cases. These results suggest that total hip resurfacing was a more valuable treatment option for active patients with ONFH than hemi-resurfacing

Background. In Japan, idiopathic osteonecrosis of the femoral head (ONFH) is designated as a specified rare and intractable disease in patients for whom medical care is subsidized through the Specified Disease Treatment Research Program. Each patient is approved for the subsidy based upon a prefectural governmental review after filing an application together with a clinical research form documenting the patient's medical history, laboratory/clinical findings, and treatment. The purpose of this study was to conduct a fact-finding study of ONFH patients in the Fukuoka Prefecture based on clinical research forms of the Specified Disease Treatment Research Program. Methods. The distribution by gender and age of ONFH patients who filed an application for subsidy under this program between 1999 and 2008 was investigated on the basis of clinical research forms in the Fukuoka Prefecture. For comparative purposes, we also investigated the distribution by gender and age of ONFH patients who had a final diagnosis of ONFH at our institution during the past three years. Results. In the Fukuoka Prefecture, 1,244 ONFH patients (758 men, 61%; and 486 women, 39%) were identified during the 10-year period. The mean age was 48 years for men and 56 years for women. Men showed a normal age distribution with a peak in their fifties, whereas, women displayed a bimodal distribution with peaks in their fifties and seventies. The numbers of patients aged greater than 60 years were 162 (21.4%) for men and 218 (44.9%) for women. At our institution, there were 94 patients (61 men, 64.9%; and 33 women, 35.1%) who had a final diagnosis of ONFH based on radiology and pathology during the 3-year period. The mean age of these patients was 44 years for mrn and 45 years for women. Men showed a bimodal distribution with peaks in their thirties and fifties, whereas, women displayed a unimodal distribution with a peak in their fifties. The numbers of patients aged greater than 60 years were 7 (11.5%) for men and 6 (18.2%) for women. The age distribution of ONFH patients in the Fukuoka Prefecture was significantly higher, particularly for women, compared with patients at our institution. Conclusion. The present study, based on clinical research forms showed that 1,244 patients were identified as having ONFH in the Fukuoka Prefecture during a 10-year period, with a men-to-women ratio of 6:4. For women, approximately half were aged greater than 60 years of age

Introduction. Hip resurfacing arthroplasty (HRA) with metal-on-metal bearing is currently emerging as a major evolution of hip arthroplasty. It could be an alternative to total hip arthroplasty. HRA also may allow young patients to perform high sports activities. It preserves proximal femoral bone stock and keeps the medullary canal intact. A large diameter of the femoral head provides wider range of the hip motion. Incidence of dislocation is very low. Most of HRA have been reported for young patients with stage of osteoarthritis. But, reports of HRA for osteonecrosis of the femoral head (ONFH) are rare and the outcomes are uncertain. Methods. This study was performed to introduce our indication and technique of HRA for the patients with ONFH and to assess the outcomes after a minimum 5-year follow up. After the biomechanical study, we set our own indications for HRA as follows: when the size of a lesion was less than 50% of the entire head and the rim at the head-neck junction was intact at least to a 5 mm above from the head-neck junction. From December 1998 to July 2004; 157 hips (139 patients) underwent HRA under the diagnosis of ONFH. Their mean age was 37 years. One hundred and fourteen hips were in men and 25 hips were in women. The average follow-up period was 88 months (range, 60 to 128 months). Clinical outcomes were evaluated with Harris Hip Scores, hip or thigh pain, limb length discrepancy, and range of motion. As a radiological evaluation, the preoperative size and staging of the lesion, patterns of bone remodeling, and complications such as femoral neck fracture, neck narrowing, loosening, and osteolysis were analyzed. Results. Sixty-two percent of the hips were staged as Steinberg IV or more. The size of the necrotic lesion in magnetic resonance imaging ranged from 23 to 50%. The Harris Hip Score increased from 77 points pre-operatively to 98 points at the final visit. All range of motions significantly improved after the operation. No patient complained of limb length discrepancy. Twenty-eight hips showed painless radiographic changes including impingement (22 hips), focal radiolucency (4 hips), and neck narrowing (2 hips). All patients showed no clinical symptoms. There was no detectable wear, dislocation, femoral neck fracture, or other complications. No revision or additional surgery was required in all patients. Conclusion. Even for the patients with ONFH, the overall minimum 5-year outcomes of HRA are promising and superior to other reports of conventional THA. Patient satisfaction is extremely high. A strict application of indications and meticulous surgical technique are critical for these successful results

Introduction. In osteonecrosis of the femoral head (ONFH), reduction in the size, or complete resolution of the necrotic lesion has been reported to occur spontaneously without any specific treatment. Recently, there was a report that the reduction was time-dependent. We evaluated the change in the size of necrotic lesions of ONFH using magnetic resonance imaging (MRI) more than 10 years after the initial diagnosis. Methods. Fifteen hips in 13 patients with atraumatic ONFH who had been followed-up for more than 10 years were enrolled in this study. They were categorized into two groups; A Simple Observation Group and a Multiple Drilling Group. The Simple Observation Group included 6 hips in 5 patients treated non-operatively. There were 3 men and 2 women who had an average age of 42 years at the time of their initial diagnosis. Initial Ficat and Arlet stages were I in 2 cases, IIA in 3 cases, and IIB in 1 case. The Multiple Drilling Group included 9 hips in 9 patients treated surgically with multiple drilling. They were all men who had an average age of 38 years at the time of operation. There were 2 cases of stage I and 7 cases of stage IIA. The necrotic lesion size change was evaluated by comparing the last follow-up MRI images with the initial images. All of the coronal, sagittal, and axial plane images were reviewed by 2 orthopaedic surgeons and a radiologist. The lesion size change was determined by means of consensus of the reviewers. The lesion size change was defined when it was detected in more than 2 planes. Results. The average time interval between the initial and last MRI imaging was 11.5 years (range, 10 to 16 years). Two cases, 1 case from each group, were excluded from the final evaluation because demarcation of the outer margin of lesion was impossible on MRI images due to severe secondary arthritic changes in the femoral head. Among the 5 cases of the Simple Observation Group, 2 cases showed a decrease in lesion size. In the Multiple Drilling Group, 5 out of 8 cases showed a decrease in lesion size and the lesion disappeared almost completely in 2 of these cases. There was no case of an increase in lesion size in both groups. Conclusion. Reduction in the lesion size of ONFH was found in some cases of long-term follow-up on MRI images. A larger portion of the cases demonstrated lesion size decrease in the Multiple Drilling Group than in the Simple Observation Group

Introduction. The goal of joint-preserving surgery for the treatment of osteonecrosis of the femoral head (ONFH) is to delay or prevent osteoarthritic development. Bone marrow is a source of osteogenic progenitors that are key elements in the process of bone formation and fracture healing. We established an easy-to-use method using a conventional manual blood bag centrifugation technique traditionally used for extracting buffy coats, for concentration of nucleated cells and platelets from clinical bone marrow aspirates to obtain osteogenic progenitors and growth factors. However, it is unclear whether the surgical goals are really achieved and if so in which patients. The purpose of this study was to identify demographic, clinical, and radiographic factors predicting total hip arthroplasty (THA) conversion after CABMAT for the treatment of idiopathic ONFH. Methods. We retrospectively reviewed 123 patients (213 hips) who had CABMAT between 2003 and 2010. Sixty-five subjects (115 hips) were male and 58 (98 hips) were female with an average age at the time of CABMAT of 40.1 years. Of the 213 hips, 143 hips in 78 patients had corticosteroid-induced ONFH, 46 hips in 27 patients had alcohol-associated, and 24 hips in 18 patients had no etiological factors could be detected. The mean follow-up period was 60.5 months. The endpoint of evaluation was set as the time point which the patient required additional surgery (THA) depending on the spontaneous hip pain, x-ray change, and social back ground. The following factors were investigated: age, sex, body mass index (BMI), unilateral or bilateral, etiological factors, preoperative classification and staging, visual analogue scale (VAS), JOA clinical score. The 213 hips were divided into two groups: a THA conversion (THA) group and a non-THA conversion (non-THA) group. A multivariate analysis was performed using a logistic regression model. Results. In this series, of the 213 hips, 51 hips (23.9%) in 37 patients converted THA. The mean age of patients in THA group was 43.0 years and that of non-THA group was 39.2 years. The mean duration between CABMAT and THA conversion was 26.9 months. Preoperatively, 11 of the 213 hips were classified as type A, 8 hips as type B, 78 hips as type C1, and 116 hips as type C2. 48 hips were classified as stage 1, 65 hips as stage 2, 58 as Stage 3A, 34 as Stage 3B, 8 as stage 4. Postoperatively, no hips in types A and B, 11 hips (14.1%) in type C1, 40 hips (34.5%) in type C2, and 8 hips (16.7%) in stage 1, 13 hips (25.0%) in stage 2, 14 hips (24.1%) in stage 3A, 11 hips (32.4%) in stage 3B, 5 hips (62.5%) in stage 4 were converted THA. Conclusions. The strongest predictors of THA conversion after CABMAT were type, the extent of necrotic area, and age. The results suggest that what factors determine the THA conversion after CABMAT and which patients of idiopathic ONFH are appropriate for CABMAT treatment. Further careful follow-up is needed clinically, and an additional treatment strategy to improve CABMAT is currently in progress

Introduction. In osteonecrosis of the femoral head (ONFH), progression of collapse is influenced by a repair reaction, especially bone resorptive activity, around the necrotic bone. Alendronate is a potent inhibitor of bone resorption by inhibiting osteoclast activity. We performed a clinical study to test if systemic alendronate treatment would prevent the development of collapse in patients with ONFH. Methods. Thirty-three hips in 22 ONFH patients with initial ARCO Stage 1 to 3 were included. Fourteen patients (20 hips) received daily administration of oral alendronate 5mg/day (alendronate group) and 8 patients (13 hips) did not receive alendronate administration (Control group). Baseline investigations included anteroposterior and lateral plain radiographs, T1-weighted magnetic resonance imaging (MRI), and biochemical markers (urinary NTX and serum BAP). Examination of the biochemical markers were repeated at 3, 6, and 12 months, and MRI imaging was repeated at 12 months. At 3 years, clinical symptoms and findings on plain radiographs were compared between the 2 groups. Advancement of ARCO stages or increase of collapse by more than 2 mm were considered as development of collapse. Results. At baseline, there were no significant differences regarding patients' age, distribution of gender, etiology, ARCO radiographic stage, and extent of necrosis between the 2 groups. In the alendronate group, there was an early decrease of osteoclast activity (NTX) and osteoblastic activity (BAP) at 3 months, with significantly larger decrease in NTX (43%) than BAP (21%) at 12 months. At 3 years, development of collapse was observed in 7 hips (54%) of the Control group, and in 3 hips (15%) of the alendronate group. Hip pain was noted in 9 hips (69%) of the Control group, and in 6 hips (30%) of the alendronate group. There was a significant difference oncollapse development and occurrence of hip pain between the two groups (p<0.05). Signal change around the necrotic region on serial MRI images during the first 1 year was observed in 54 % of the Control group, and only 11% of the alendronate group. Conclusion. Alendronate therapy decreased biochemical markers, especially osteoclast activity, after an early period from start of administration. Several clinical studies have shown promising short-term results for prevention of collapse in ONFH by administration of bisphosphonates. The present study showed a significant preventing effect of collapse development by administration of alendronate which was maintained for 3 years of treatment. Low incidence of signal change on serial MRI images may also reflect decrease of repair activity in the alendronate group. Further studies with longer follow-up, larger numbers of patients, and randomized administration of the drug among patients are required., However, alendronate administration may become one of the effective conservative treatments which might obviate the need for osteotomy or replacement surgery in some populations of ONFH patients