Core Decompression for Avascular Necrosis
Number: 0753
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Aetna considers core decompression medically necessary for the treatment of early/pre-collapse (stage I or II; before X-ray changes are evident) avascular necrosis of the hip (femoral head and/or neck).
Aetna considers core decompression experimental and investigational for the treatment of the following indications (not an all-inclusive list) because its effectiveness for these indications has not been established.
- Avascular necrosis of other joints (e.g., the ankle, elbow, knee, mandibular condyle, and shoulder)
- Late/post-collapse (stage III or higher; when X-ray changes have occurred) avascular necrosis of the hip
- Post-arthroscopic osteonecrosis
Aetna considers the following adjunctive treatments experimental and investigational for the treatment of avascular necrosis of any joint because the effectiveness of these approaches has not been established (not an all-inclusive list):
- Autologous bone marrow mononuclear cells/bone marrow concentrate/bone marrow stem cells
- Autologous platelet concentrate
- Bisphosphonates
- Bone morphogenic proteins (e.g., rhBMP-2)
- Demineralized bone matrix
- Erythropoietin
- Extracorporeal shockwave
- Growth factors
- Intraosseous ibandronate
- Laser therapy
- Mesenchymal stem cells
- Ozone therapy
- Parathyroid hormone
- Platelet-rich fibrin
- Platelet-rich plasma (PRP)
- PRP combined with stem cells
- PRP combined with mesenchymal stem cells and synthetic bone graft
- Synthetic bone graft substitute (e.g., calcium sulphate and calcium phosphate).
Note: According to the Ficat Classification of Avascular Necrosis of the Femoral Head, the presence of cysts is considered stage II. (Ficat Classification of Avascular Necrosis (AVN) of the Femoral Head).
See also:
- CPB 0172 - Hyperbaric Oxygen Therapy (HBOT)
- CPB 0287 - Hip Arthroplasty
- CPB 0661 - Joint Resurfacing.
Background
Avascular necrosis (AVN), also known as osteonecrosis, aseptic necrosis and ischemic bone necrosis, is a relatively common disease characterized by death of cellular elements of bone or marrow. Most of the 10,000 to 20,000 Americans who develop AVN annually are between the ages of 20 and 50 years. The hip (femoral head) is the most commonly affected site for clinically significant AVN. There are many risk factors for the disease including hemoglobinopathies, dislocation of the hip, alcoholism, fracture of the femoral neck, use of corticosteroid, as well as collagen vascular disease. With secondary collapse of the femoral head, disabling hip pain may result in the need for total hip replacement. For non-traumatic AVN, the disease is often bilateral, which further increases the extent of disability. Various approaches have been employed for treating different stages of AVN of the hip. Non-operative treatments include rest, non-weight-bearing exercises, protected weight-bearing, pharmacotherapy (e.g., non-steroidal anti-inflammatory drugs and bisphosphonate medications such as alendronate or residronate), and electrical stimulation. Operative treatments include fusion, osteotomy, hemi-resurfacing, hemi-arthroplasty, debridement and grafting, core decompression with or without grafting, as well as total hip arthroplasty (Shannon and Trousdale, 2004; DeSmet et al, 2005; McKown, 2007).
Core Decompression of the Hip
Core decompression of the hip is usually employed before collapse and fracture of the femoral head and/or neck to delay or avoid reconstructive surgery of the affected joint. It is generally carried out to preserve the function and the structure of the hip as well as to relieve pain associated with AVN. Core decompression entails repair of the necrotic site by coring, followed by filling the cored area with a bone graft, which is optional. A lateral trochanteric approach is used in this procedure: an 8-mm to 10-mm cylindrical core of bone is removed from the antero-lateral segment of the femoral head, which creates an open cylindrical channel. This open channel serves to relieve pressure. The open channel may be filled with either a vascularized or a non-vascularized bone graft. The former is used to aid in the ingrowth of vascular cellular tissue into the necrotic area; thus enhancing re-vascularization, which may arrest the progression of the necrosis. The latter is used to provide structural stability to the hip during the healing process. There is adequate evidence that core decompression is effective in treating early stages (I or II) of AVN of the hip.
Castro and Barrack (2000) performed a metaanalysis of data on core decompression and conservative treatment for avascular necrosis (AVN) of the femoral head. MEDLINE was searched from 1966 to 1998 using the MeSH terms 'femoral head necrosis' and 'osteonecrosis', and the reference from retrieved articles were examined for additional studies. The search was restricted to citations in the English language. Study designs of evaluations included in the reviewStudies with at least 10 participants and a minimum average follow-up of 12 months were eligible for inclusion. Studies where patient selection protocols created sample biases were excluded. The average length of follow-up was 43 months (SE=6 months). Surgical core decompression, i.e. the removal of a single core of bone from the avascular segment of the femoral head, was compared with conservative treatment, i.e. a period of protected weight bearing with crutches. Studies in which participants received additional treatments, such as iliac crest bone graft, vascularised fibular grafting, or pulsed electromagnetic stimulation, in addition to core decompression, were excluded from the analysis. Patients with AVN of the femoral head, as determined by radiographic staging according to the Steinberg classification (stages 0 to V) or an equivalent classification system were included. The three most common causes of AVN were steroid use (344 hips), alcohol abuse (153 hips) and idiopathic (127 hips). The average age of the participants presenting was 40 years (standard error, SE=2 years). Bilateral disease was present in 31% of the participants undergoing core decompression and in 62% of those undergoing conservative treatment. Successful treatment, defined as no further surgical intervention implemented or recommended, was assessed. Radiographic progression from stage I to stage II was not considered a failure, since radiographs significantly lag behind the physiological condition in the femoral head. Steinberg stage 0 outcomes were not compared since prophylactic core decompression of an asymptomatic, normal hip was not recommended by most authors. The stage III hips were not compared because their advanced disease predisposes them to failure, regardless of the intervention. A meta-analysis was performed to compare the success rates for core decompression and conservative treatment for Steinberg stages I and II. A sensitivity analysis was used to compare the 22 studies included in the meta-analysis with the 9 studies excluded on account of highly selected patient groups; this compared year of publication, distribution of Steinberg stages, and percentage of bilateral cases. The sensitivity analysis was performed in order to determine whether the variables used to select patients were predictive of core decompression failure. Twenty-two studies (n=818) using a single surgical core decompression technique, and 8 studies (n=264) using a conservative technique, were included. Eleven studies were non-randomised prospective, 10 were retrospective, and 1 was randomized prospective. An additional 9 studies that were excluded on account of highly selected patient groups were used in a further sensitivity analysis. The most significant finding was that, with an average follow-up time of 42 months, core decompression was 23% more successful than conservative treatment for hips with Steinberg stage I AVN. The success rates for surgical core decompression were 84, 63 and 29% for Steinberg stages I, II, and III, respectively. Conservatively- treated patients with stage 0, I, II and III AVN demonstrated success rates of 86, 61, 59 and 25%, respectively. Chi-squared analysis showed that for stage I hips only, the success rate of core decompression (84%) was statistically significantly higher than that for conservative treatment (61%) (p=0.001). Several significant differences were found in the sensitivity analyses. Studies with selection biases tended to be performed earlier than non-biased studies (1,986 versus 1,992; p=0.0068). Studies on specific groups also had proportionately fewer patients in Steinberg stage I (21 versus 48%; p=0.02), more patients in Steinberg stage III (42 versus 18%; p=0.03), and more patients with bilateral disease (86 versus 31%; p=0.0001). When 70% or more of the sample patients had bilateral disease, the success rates for Steinberg stages I, II and III were 50, 60 and 44%, respectively. There were 33 (5%) complications in the 688 cases reported in the 13 studies. Reported complications were intertrochanteric fracture (n=14), technical errors in surgery (n=6), seromas and wound infections (n=8), femoral head fractures (n=3), deep vein thrombosis (n=1) and pulmonary embolus (n=1). The authors state that the 23% difference between core decompression and conservatively-treated patients with Steinberg stage I AVN was interpreted cautiously. Although many authors agree that core decompression provides excellent and immediate pain relief, core decompression did not alter the progression of AVN in Steinberg stage II hips.
Steinberg (1995) evaluated the safety and effectiveness of core decompression in the treatment of AVN of the femoral head. All patients with AVN of the femoral head, stages I to IVA, were included regardless of the cause of the necrosis. A total of 300 hips were available for analysis. The follow-up ranged from 2 to 12 years. Main outcome measures included antero-posterior and lateral radiographs, taken immediately before surgery and at the final follow-up, clinical hip evaluation according to the Harris scoring system, and the need for total hip replacement. One patient sustained a subcapital fracture 1 month after surgery due to a fall. There was 1 case of non-fatal pulmonary embolism, 1 case of pneumonia, and 1 case of thrombo-phlebitis of the thigh. A total of 46 % of operatively managed hips showed no radiographical progression of disease compared with only 19 % of non-operatively managed hips. Moreover, 35 % of the operatively managed hips required total hip replacement compared with 77 % of non-operatively managed hips. The results in hips with early (stages I and II) AVN were only slightly better than those of hips with advanced (stages III and IVA) disease. However, the results in hips with small areas of necrosis in both stages I and II were much better than those with larger lesions; only 7 % of the former group required total hip replacement after decompression and cancellous bone grafting. The authors concluded that core decompression with cancellous bone grafting is a safe and effective procedure for the treatment of early AVN of the femoral head. Results with this form of treatment are considerably better than those obtained in patients treated non-operatively.
Steinberg et al (2001) reviewed the results of a prospective study of 406 hips in 285 patients treated by one surgeon with core decompression and bone grafting. Patients were followed-up for 2 to 14 years. The outcome was determined by the change in the Harris hip score, quantitative radiographical measurements, and the need for total hip replacement. These hips were compared with 55 hips in 39 patients treated non-operatively and with historic controls. Five complications occurred after 406 procedures including 2 fractures that resulted from falls during the first post-operative month. Of the 312 hips in 208 patients with a minimum 2-year follow-up, 36 % of hips (113 hips in 90 patients) required hip replacement at a mean of 29 months: 18 of 65 hips (28 %) with stage I disease; 45 of 133 hips (34 %) with stage II disease; 3 of 13 hips (23 %) with stage III disease; and 45 of 92 hips (49 %) with stage IV disease. Before femoral head collapse (stages I and II combined) hip replacement was performed in 10 of 77 hips (14 %) with small lesions, 33 of 68 hips (48 %) with intermediate lesions, and 20 of 48 hips (42 %) with large lesions. Results as determined by changes in Harris hip scores and radiographical progression were similar. Patients who underwent core decompression and bone grafting have a very low complication rate. In patients treated before femoral head collapse, the outcome is significantly better than in patients who received symptomatic treatment. The results were correlated with the stage and the size of the necrotic lesion.
Simank et al (2001) assessed and compared the results of core decompression and inter-trochanteric osteotomy for non-traumatic osteonecrosis of the femoral head using Cox regression and survivorship analysis. A total of 177 cases with a mean age of 41 years at surgery were treated for osteonecrosis (94 core decompressions and 83 osteotomies). Any further surgery was defined as failure and endpoint. Significant risk factors for treatment failure were age over 40 years at surgery (p = 0.022), corticosteroid intake (p < 0.001), advanced stage of necrosis (Steinberg stage greater than or equal to III, p = 0.04), and core decompression (p = 0.084). To analyze the influence of the surgical procedure, patients with corticosteroid treatment were excluded, and survival analysis was performed. This analysis revealed survival rates of 74 % after osteotomy and 78 % after core decompression 6 years post-operatively in early, pre-collapse stages (p = 0.819). In advanced stages, the rate of survival for hips after core decompression was lower (56 %) than in hips after osteotomy (76 %) (p = 0.056). These findings indicated that core decompression may be as effective as inter-trochanteric osteotomy in pre-collapse stages but is less traumatizing and is cost-effective. For post-collapse hips, inter-trochanteric osteotomy should be considered.
Bellot and associates (2005) studied retrospectively a series of 32 cases (25 patients) of femoral head osteonecrosis treated by core decompression. These researchers examined the epidemiological and clinical features as well as the laboratory findings, and compared cases requiring secondary hip replacement and those that had a favorable outcome. The series included 32 hips, 1 case was lost to follow-up. Mean age at decompression was 41.3 years (22 to 55). In 8 hips, osteonecrosis was favored by corticosteroid treatment, in 3 by chronic alcoholism, and in 1 by hypertriglyceridemia. No favoring factors were present for 20 hips. According to the Association Research Circulation Osseous (ARCO) classification there were 15 stage I hips, 13 stage II, 3 stage III, and 1 stage IV. Core decompression was centered in 24 hips and mean time to decompression was 6.4 months (14 days to 40 months). These investigators reviewed hips without a total prosthesis using the Postel-Merle-d'Aubigne function score and for the radiological assessment the ARCO stage and the Koo index. Favorable outcome was noted in 12 hips. Total hip arthroplasty was required for 19, 1 hip was lost to follow-up. Mean follow-up in the success group was 82 months (26 to 176) and mean "time of participation" in the failure group was 11 months (1 to 38). Mean survival after core decompression was 14 months. Time between onset of symptoms and decompression did not influence outcome. Lesions that remained asymptomatic before decompression remained stable. Stage I hips did not have more favorable outcome than stage II hips (p < 0.05). Stage III or IV hips had unfavorable outcome. Hips with a Koo index greater than 40 had a poor outcome (p < 0.05). The authors concluded that early disease (stage I or II) is an ideal indication for decompression, but is insufficient alone to guarantee success. Furthermore, they considered late disease (stage III or IV and a Koo index greater than 40) an contraindication for decompression.
Israelite and co-workers (2005) stated that early treatment of osteonecrosis of the femoral head yielded better results than late treatment. Because osteonecrosis is frequently bilateral, it often is advisable to treat both hips simultaneously. Core decompression is one of the more common methods of treatment; however the safety of doing simultaneous bilateral core decompression has been questioned. These researchers sought to evaluate the safety and effectiveness of simultaneous bilateral core decompression compared with unilateral core decompression. A total of 193 patients (276 hips) who had core decompression with bone grafting were followed up for 24 to 145 months; 124 procedures were unilateral and 152 were bilateral. Patients were evaluated by change in Harris hip score, radiographical progression, post-operative complications, and conversion to total hip arthroplasty. Total hip arthroplasty was required in 56 of 124 (45 %) of hips in the unilateral, and 48 of 152 (32 %) of hips in the bilateral group. Post-operative complications were similar. In the unilateral group there were 2 major and 9 minor complications; in the bilateral group there were 3 major and 10 minor complications. When bilateral core decompression is indicated, it can be done simultaneously on both hips, allowing earlier treatment of the contralateral hip without risk of increased complications and possibly with a better outcome. Simultaneous bilteral deompression required only one hospitalization and decreased recovery time compared with two separate procedures. Therefore, it provided advantages over procedures that can not be done simultaneously on both hips.
Keizer and associates (2006) described the long-term results of core decompression and placement of a non-vascularized bone graft in the management of AVN of the femoral head. These investigators treated 80 hips in 65 patients, 18 by a cortical tibial autograft and 62 by a fibular allograft. The mean age of the patients was 36 years. A total of 78 hips were available for evaluation of which pre-operatively 6 were Ficat-Arlet stage 0, 3 stage I, 31 stage IIA, 16 stage IIB, 13 stage III and 9 stage IV. A total of 34 hips (44 %) were revised at a mean of 4 years (standard deviation [SD] 3.8). Survivorship analysis using a clinical end-point showed a survival rate of 59 % 5 years after surgery. These researchers found a significant difference (p = 0.002) in survivorship, when using a clinical and radiological end-point, between the 2 grafts, in favor of the tibial autograft. They considered this difference to be the result of the better quality and increased volume of tibial bone compared with that from the trochanteric region used with the fibular allograft. This is a relatively simple, extra-articular and reproducible procedure. In the authors' view core decompression, removal of the necrotic tissue and packing of the cancellous grafts into the core track are vital parts of the procedure.
von Stechow and Drees (2007) stated that osteonecrosis of the femoral head eventually leads to its destruction if it remains untreated. Depending on the location and the extent of the osteonecrosis, several surgical options are available. For early small and medium-sized pre-collapse lesions, core decompression is the treatment of choice. Osteotomies and bone grafting procedures can be utilized in medium pre-collapse, as well as in small post-collapse lesions. Cartilage lesions of the femoral head allow limited femoral resurfacing arthroplasty. If the acetabulum reveals cartilage lesions, a total hip replacement should be preformed.
Mont and co-workers (2007) noted that when osteonecrosis of the femoral head is diagnosed in its early stages (before collapse of the femoral head), various procedures such as core decompression (with and without bone grafting), osteotomies, as well as non-vascularized and vascularized bone grafting can be used to preserve the joint. The effectiveness of core decompression has been peer-reviewed in more than 40 studies. In general, this treatment is most successful for patients with early stage, small- and medium-sized lesions, before collapse of the femoral head. Various methods of non-vascularized bone grafting have been used. Results have varied; however, a 60 % to 80 % success rate has been achieved at 5- to 10-year follow-up.
Other techniques such as infusion/implantation of autologous bone-marrow mononuclear cells (BMMC) have also been used in an attempt to improve the outcomes of core decompression.
Gangji and Hauzeur (2005) studied the implantation of autologous BMMC in a necrotic lesion of the femoral head to determine the effect on the clinical symptoms and the stage and volume of osteonecrosis. They studied 13 patients (18 hips) with stage I or II osteonecrosis of the femoral head, according to the ARCO classification. The hips were allocated to a program of either core decompression (the control group) or core decompression and implantation of autologous BMMC (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. After 24 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 Western Ontario and McMaster Universities Arthritis Index (p = 0.013) within the bone-marrow-graft group. At 24 months, 5 of the 8 hips in the control group had deteriorated to stage III, whereas only 1 of the 10 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 BMMC was associated with only minor side effects. The authors concluded that implantation of autologous BMMC appeared 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.
Yan and colleagues (2006) assessed the safety and effectiveness of the treatment of osteonecrosis of the femoral head by percutaneous decompression and autologous BMMC infusion. A total of 44 hips in 28 patients with AVN at early stage were treated by percutaneous multiple holes decompression followed by autologous BMMC infusion. Autologous BMMC were concentrated from bone marrow that was taken from the posterior iliac crest of the patient. Patients were followed-up at least 2 years. Results were determined by the changes in the Harris hip score and the progression in the radiographical stages. No complications were observed after the operation. Before operation, there were stage I of femoral head necrosis in 8 hips, stage II in 15 hips, stage III in 14 hips, stage IV in 7 hips, and the post-operative stages at the most recent follow-up were stage O in 1 hip, stage I in 6 hips, stage II in 13 hips, stage III in 13 hips, stage IV in 7 hips, stage V in 4 hips. The mean pre-operative Harris hip score was 58 (46 to 89), and improved to 86 (70 to 94) post-operatively. All the femoral head collapsed pre-operatively showed that the necrotic size was at least more than 30 %. The authors concluded that percutaneous multiple holes decompression combined with autologous BMMC is a new way to treat AVN of the femoral head. The earlier the stage, the better the result. They noted that randomized prospective studies are needed to compare this combination approach with routine core decompression.
Gangji et al (2011) examined the effectiveness 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. These investigators studied 19 patients and 24 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. Bone marrow implantation afforded a significant reduction in pain and in joint symptoms and reduced the incidence of fractural stages. At 60 months, 8 of the 11 hips in the control group had deteriorated to the fractural stage whereas only 3 of the 13 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 2 groups at 60 months. Patients had only minor side effects after the treatments. The authors concluded that 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.
In a Cochrane review on the treatment for AVN of bone in individuals with sickle cell disease (SCD), Martí-Carvajal and colleagues (2009) found no evidence that adding hip core decompression to physical therapy achieves clinical improvement compared to physical therapy alone. However, these investigators highlighted that their conclusion was based on 1 trial with high attrition rates. They stated that further randomized controlled trials are needed to assess the role of hip-core depression for this clinical condition. Endpoints should focus on participants' subjective experience (e.g., quality of life and pain) as well as more objective "time-to-event" measures (e.g., mortality, survival, hip longevity).
Bakhshi and colleagues (2012) stated that osteonecrosis of femoral head (ONFH) is a challenging disease. Regardless of underlying causes, the ultimate result in all cases is disruption of femoral head blood supply. Once the disease starts, it is progressive in 80 % of cases. Since the majority of the affected individuals are young, every effort should be focused on preserving the patients own femoral head. In recent years, the role of angiogenic growth factors has been studied with promising results in animal models of ONFH. Erythropoietin (EPO) is a well-known hormone that has been used in treatment of chronic anemia for many years with few side effects. Considering the angiogenic properties of EPO, the authors hypothesized that local delivery of recombinant human EPO during core decompression will enhance bone regeneration in ONFH.
Helbig et al (2012) evaluated patients after core decompression combined with an augmentation by a demineralized bone matrix, and particularly aimed to report long-term conversion rates to total hip replacement (THR). A total of 14 patients with 18 hips suffering from ONFH (Ficat stage I to IIB) underwent this surgical procedure. All patients underwent radiographical and magnetic resonance imaging (MRI) investigations at baseline and at follow-up periods of 12 and 24 months. The clinical follow-up was done using the Merle d'Aubigné-score for an average period of 9 years after surgery. Fourteen of the 18 subjects (77 %) achieved at least a good clinical result after 2 years. The Merle d'Aubigné-score improved significantly after 12 (p = 0.0001) and 24 months (p = 0.0002). However, the MRI volumetric analysis showed an increased necrotic bone volume from 3.16 +/- 0.54 to 3.88 +/- 0.62 cm(3) (p = 0.04). Within 9 years, 13 out of 18 cases (72 %) required further surgery by THR. Only 7 out of 18 subjects (39 %) reported an ongoing post-operative clinical benefit, and would retrospectively redo the same surgical approach again. The 5 patients who did not require THR were still satisfied after 9 years. Theauthors concluded that in patients with early-stage ONFH, core decompression combined with the implantation of a demineralized bone matrix leads to a limited, temporary pain relief as seen in core decompression alone. However, long-term results were not encouraging with a high rate of conversion to arthroplasty. Therefore, core decompression with implantation of a demineralized bone matrix may be not appropriate to avoid THR in the long-term.
Wang et al (2012) examined the effectiveness of core decompression surgery for the treatment of steroid-induced femoral head osteonecrosis. The rabbit femoral head osteonecrosis model was established by the administration of steroids in combination with horse serum. Magnetic resonance imaging was applied to screen for the animal femoral head osteonecrosis. The rabbits with bilateral femoral head osteonecrosis were randomly selected to do the one side of core decompression. The other side was used as the sham. Quantitative reverse transcription polymerase chain reaction (RT-PCR) and western blot techniques were used to measure the local expression of bone morphogenetic protein-2 (BMP-2) and peroxisome proliferator-activated receptor gamma (PPAR-gamma) mRNAs and proteins. Bone tissues of femoral head from the normal control group and operation group (with or without lateral decompression) were histologically analyzed by H and E staining. The comparisons of the local expression of BMP-2 and PPAR-gamma mRNAs and proteins and the bone regeneration were further analyzed between different groups at each time point (2, 4 and 8 weeks post-operation, respectively). The expression of BMP-2 mRNA and protein in the steroid-induced femoral head osteonecrosis with or without core decompression was significantly lower than that in normal animals. And BMP-2 expression in femoral head osteonecrosis with and without lateral decompression both showed the decreasing trend with the increased post-operation time. There was no significant difference of BMP-2 expression between femoral head osteonecrosis with and without lateral decompression. The expression of PPAR-gamma mRNA and protein in steroid-induced femoral head osteonecrosis with and without core decompression both were significantly higher than that in normal animals. The PPAR-gamma expression in the steroid-induced femoral head osteonecrosis with and without lateral decompression both showed a significantly increased trend with the increased post-operation time. However, there was no significant difference of PPAR-gamma expression between the femoral head osteonecrosis with and without lateral decompression at each time point. Histopathological analysis revealed that new trabecular bone and a large number of osteoblasts were observed in the steroid-induced femoral head osteonecrosis with lateral decompression at 8 weeks after surgery, but there still existed phenomenon of trabecular bone fractures and bone marrow cell necrosis. The authors concluded that although core decompression takes partial effect in promoting bone regeneration in the early treatment of femoral head osteonecrosis, such an effect does not significantly improve or reverse the pathological changes of femoral marrow cell necrosis. Thus, the long-term effect of core decompression in the early treatment of steroid-induced femoral head osteonecrosis is not satisfactory.
Guadilla et al (2012) described a non-invasive arthroscopic procedure as an alternative to open surgery for avascular necrosis of the hip. Patients with grade I or IIA AVN of the hip were treated by core decompression performed by drilling under fluoroscopic guidance. Liquid platelet-rich plasma (PRP) is delivered through a trocar, saturating the necrotic area. In more severe conditions, the necrotic bone is decompressed and debrided, through a cortical window at the head-neck junction. A composite graft made of autologous bone and PRP is delivered by impactation through the core decompression track. Fibrin membranes were applied to enhance healing of the head-neck window and arthroscopic portals. Platelet-rich plasma was infiltrated in the central compartment. This arthroscopic approach aided in making diagnosis of the labrum and articular cartilage and allowed intra-operative treatment decisions. Visual control provided the precise localization and treatment for the necrotic area allowing cartilage integrity to be preserved. The authors concluded that arthroscopic management of AVN of the femoral head is viable and has significant advantages. They stated that clinical studies should justify the theoretical additional benefits of this approach.
Abrisham et al (2013) examined the value of core decompression in treating the AVN; this study was performed on patients with symptomatic AVN with different etiologies who were treated with core decompression. This study was carried out on 25 patients (with the total number of 37 femoral head) who were diagnosed AVN using X-ray and MRI. Core decompressions for these patients were started soon after the diagnosis. The results were considered as a success if there was no progression of disease confirmed by X-ray or no subsequent operation was required. Modified Ficat staging was used to record changes before and 2 years after core decompression treatment. Twenty five patients were participated in this study in which 68 % (n = 17) were female, 32 % (n = 8) were male, and the average of the age of the patients were 29.58 ± 4.58. Eight of these patients had systemic lupus erythematous (SLE) (32 %), 4 rheumatoid arthritis (RA) (16 %), 3 with kidney transplant (12 %), 1 Takayasu's vasculitis (4 %) and 1 Wegner vasculitis (4 %). Eight of patients had a history of intravenous injection of Temgesic (32 %). In patients using Temgesic the changes in Modified Ficat staging were significantly different before and after core decompression (p = 0.03) in comparison with other groups; and in all 8 Temgesic users AVN progressed to the stage 3 and 4 after core decompression. The authors concluded that this study demonstrated that core decompression to prevent the changes in the femoral head has been more effective in patients with collagen vascular diseases and kidney transplant than patients using intravenous Temgesic. These patients, in spite of early operation, showed no benefit of core decompression to prevent the changes in the femoral head.
Zalavras and Lieberman (2014) stated that osteonecrosis of the femoral head may lead to progressive destruction of the hip joint. Although the etiology of osteonecrosis has not been definitely delineated, risk factors include corticosteroid use, alcohol consumption, trauma, and coagulation abnormalities. Size and location of the lesion are prognostic factors for disease progression and are best assessed by MRI. The effectiveness of medical management of osteonecrosis with pharmacologic agents and biophysical modalities requires further investigation. Surgical management is based on patient factors and lesion characteristics. Preservation of the femoral head may be attempted in younger patients without head collapse by core decompression with vascularized bone grafts, avascular grafts, bone morphogenetic proteins, stem cells, or combinations of the above or rotational osteotomies. The authors concluded that the optimal treatment modality has not been identified. When the femoral head is collapsed, arthroplasty is the preferred option.
Core Decompression of Other Joints (e.g., Knee, Ankle, and Shoulder)
- spontaneous osteonecrosis of the knee (SPONK), and
- secondary osteonecrosis of the knee.
While available evidence indicates that core decompression is effective in treating early stages of AVN of the hip, there is currently insufficient evidence that this procedure is effective in treating AVN of the knee, ankle, and shoulder. The quality as well as the quantity of the evidence for core decompression for these joints is poor and limited. In particular, the majority of studies involved a small number of patients and lacked appropriate control groups. Furthermore, several of the studies were pulbished by the same group of investigators. Prospective, well-designed, randomized, controlled trials are needed to ascertain the clinical value of core decompression for joints other than the hip.
Jacobs et al (1989) performed 28 core decompressions of the distal femur for pathologically confirmed AVN. At a mean follow-up of 54 months (range of 20 to 140 months) and using the Ficat stages, all 7 cases in stage I and stage II had good results. Of 21 cases in stage III, 11 cases had good results, 4 had poor results, and 6 needed total knee replacement. There were no significant orthopedic complications. The authors noted that core decompression is worthwhile and will be more accurate with new methods of imaging.
Mont and colleagues (1997) reported the long-term results of core decompression for the treatment of AVN of the distal femur. A total of 79 knees (45 patients) were evaluated. All patients had a corticosteroid association (had been treated with more than 30 mg of prednisone for over 2 weeks predating by at least 6 months the onset of AVN). A total of 32 knees were managed with rest and protected weight-bearing. Core decompression was performed at a minimum of 3 months after the onset of symptoms in another 47 knees. Knees treated with protected weight-bearing had an average asymptomatic period of only 11 months and all but 6 (18 %) proceeded to total knee replacement within 6 years. Core decompression yielded good or excellent results in 73 % of the knees at an average follow-up of 11 years (range of 4 to 16 years). Of the 13 knees with failed core decompression, 7 were asymptomatic for greater than 5 years. A subset of 26 knees from each group was matched for age, gender, diagnosis, Ficat and Arlet Stage, and length of follow-up. The matched non-core group had 23 % survival as compared with 74 % survival in the core group. These long-term follow-up findings suggested that core decompression may slow the rate of symptomatic progression of AVN of the knee. Furthermore, core decompression may extend the symptom-free interval in certain patients and may delay the need for more extensive procedures such as total knee arthroplasty.
Forst et al (1998) reported their findings on early core decompression in patients with spontaneous AVN of the knee/femoral condyle. In 16 patients with an average age of 64.6 +/- 9.8 years and sudden onset of severe knee pain, the initial stage of Ahlbäck disease (spontaneous AVN of a femoral condyle) was verified by MRI and subsequent histology. The first radiological sign of AVN (flattening of the affected femoral condyle) was present in only 1 case. All patients were treated surgically by extra-articular drilling into the affected femoral condyle to achieve core decompression. Knee pain disappeared immediately after surgery in all patients. Successful healing was confirmed by normalization of the bone marrow on MRI (on average, 35.8 months follow-up). Core decompression by extra-articular drilling into the femoral condyle can be recommended as an effective treatment in initial AVN of the knee (still radiologically invisible). However, if radiological flattening of the affected femoral condyle becomes apparent, progression of this disease can not be avoided.
Mont et al (2000a) defined the clinical, demographical, and radiographical patterns of atraumatic AVN of the distal part of the femur and the proximal part of the tibia at presentation and reported the outcome of treatment of this condition. A total of 248 knees in 136 patients who were younger than the age of 55 years were treated. Results of non-operative treatments, core decompression, arthroscopic debridement, and total knee arthroplasty were evaluated. There were 106 female patients and 30 male patients, and their mean age was 36 years (range of 15 to 54 years) at the time of diagnosis. A total of 101 patients (74 %) had involvement of other large joints, with 18 (13 %) presenting initially with knee symptoms. A total of 101 patients (74 %) had a disease that affected the immune system; 67 of them had systemic lupus erythematosus. A total of 123 patients (90 %) had a history of corticosteroid use. Technetium-99m bone-scanning missed lesions in 16 (29 %) of 56 knees. Eight (20 %) of 41 initially symptomatic knees treated non-operatively had a successful clinical outcome (a Knee Society score of at least 80 points and no additional surgery) at a mean of 8 years. The knees that remained severely symptomatic for 3 months were treated with either core decompression (91 knees) or total knee arthroplasty (7 knees). Seventy-two (79 %) of the 91 knees treated with core decompression had a good or excellent clinical outcome at a mean of 7 years. Efforts to avoid total knee arthroplasty with repeat core decompression or arthroscopic debridement led to a successful outcome in 15 (60 %) of 25 knees. Thirty-four (71 %) of 48 knees treated with total knee arthroplasty had a successful clinical outcome at a mean of 9 years. The authors concluded that atraumatic AVN of the knee affects women predominantly, and was associated with corticosteroid use in 90 % of the patients. Evaluation should include standard radiographical and MRI of all symptomatic joints. Prognosis was negatively related to large juxta-articular lesions. Non-operative treatments should be reserved for asymptomatic knees only. Core decompression was successful (a Knee Society score of at least 80 points and no additional surgery) in 79 % of the knees in which the disease was in an early stage. Total knee arthroplasty was successful in only 71 % of the knees.
Delanois et al (1998) reported their findings of 37 ankles in 24 patients who were treated for atraumatic AVN of the talus. There were 21 women and 3 men, and their mean age was 40 years (range of 26 to 62) at the time of the diagnosis. Thirteen (54 %) of the 24 patients had bilateral involvement. Sixteen patients (67 %) had a disease that affects the immune system, including systemic lupus erythematosus (n = 13), scleroderma (n = 1), insulin-dependent diabetes mellitus (n = 1), and multiple sclerosis (n = 1). Four patients had a history of regular alcohol use, and 4 patients had a history of moderate smoking. One patient had a protein-S deficiency, 1 patient had had a renal transplant, and 1 patient had a history of asthma. Two patients had no identifiable risk factors for osteonecrosis. Fifteen patients (63 %) had involvement of other large joints. The mean duration of symptoms before the patients were seen was 5.4 months (range of 2 months to 2 years). The mean ankle score at the time of presentation was 34 points (range of 2 to 75) according to the system of Mazur et al. A radiographical review revealed that, according to the system of Ficat and Arlet, 8 ankles had stage III or IV disease of the talus at presentation. The remaining 29 ankles had stage II disease. Osteonecrosis was seen in the postero-lateral aspect of the talar dome (zones III and IV on the sagittal images; and zones II, III, and IV on the coronal images) in 22 of the 23 ankles for which MRI were available. Osteonecrosis was seen in the antero-medial aspect of the talar dome (zones I and II on the sagittal images; and zone I on the coronal images) in the remaining ankle. Bone scans, available for 11 ankles, revealed increased uptake in the talus. All patients were initially managed non-operatively with restricted weight-bearing, an ankle-foot orthosis, and use of analgesics; 2 ankles responded to this regimen. Thirty-two ankles that remained severely symptomatic were treated with core decompression, which was useful in the treatment of pre-collapse (stage II) disease. Twenty-nine of these ankles had a fair-to-excellent clinical outcome a mean of 7 years (range of 2 to 15 years) post-operatively; the remaining 3 ankles had an arthrodesis after the core decompression failed. Three ankles were treated initially with an arthrodesis for post-collapse (stage III or IV) disease. All 6 of the ankles that had an arthrodesis fused, at a mean of 7 months (range of 5 to 9 months) post-operatively.
Mont et al (2000b) described the epidemiology, clinical and radiographical presentation, treatment, and prognosis of atraumatic AVN of the shoulder/humeral head. Of the 1,056 patients managed for AVN of any joint between July 1, 1974, and December 1, 1996, 127 shoulders in 73 patients were treated for atraumatic AVN of the proximal humerus. There were 47 women and 26 men with a mean age of 41 years (range of 20 to 60). Numerous associated factors were noted: alcohol use (38 %), moderate smoking (30 %), asthma (8 %), and nephrosis (3 %). A corticosteroid association was noted in 60 patients (82 %) and 42 of the patients (58 %) had an immuno-compromising disease. The severity of humeral head AVN did not correlate with dose or duration of corticosteroid therapy. According to the modified Ficat and Arlet radiographical staging system, there were 20 shoulders with Stage I disease, 55 shoulders with stage II disease, and 52 shoulders with Stage III or IV disease. Seventy-four of the shoulders treated with core decompression (78 %) had good to excellent clinical outcomes at a mean follow-up of 6 years (range of 2 to 21). Fourteen of the 16 patients (88 %) treated with hemi-arthroplasty or total shoulder arthroplasty were clinically successful at a mean follow-up 4 years (range of 2 to 11). The authors concluded that there was a low incidence of humeral head involvement in the AVN patient cohort (7 % of all AVN patients), and a high incidence of corticosteroid use (82 %), hip involvement (81 %), and bilateral disease (74 %).
Harreld et al (2009) stated that osteonecrosis of the humeral head is considerably less common than osteonecrosis of the hip. However, as in the hip, the interaction between a genetic predisposition and certain risk factors may lead to increased intra-osseous pressure, loss of circulation, and eventual bone death. The most common risk factor remains corticosteroid use, which accounts for most reported cases. Radiographical staging and measurement of lesion size are predictive of disease progression and can be used to determine appropriate intervention. Recent studies have reported the use of various treatment modalities such as pharmacotherapy, core decompression with small-diameter drilling, arthroscopic-assisted core decompression, as well as bone grafting. The authors concluded that prospective, randomized trials are needed to determine the effectiveness of these joint-preserving procedures. Hemiarthroplasty and total shoulder arthroplasty are recommended for patients with end-stage disease.
Innes and Strauch (2010) performed a systematic review of the treatment of Kienbock's disease to test the hypothesis that none of the reported treatments for Kienbock's disease is superior with respect to outcomes of pain, motion, grip strength, and radiographic measures. These investigators searched PubMed, Medline, and the Cochrane Review for articles published between 1998 and 2008 reporting outcomes of treatment for Kienbock's disease. Patients were grouped by stage of disease. Early stages were defined as Lichtman stage I, II, and IIIa, and "late" stages as IIIb and IV. The groups were then analyzed on the basis of treatment; procedures performed on subjects in the early group included vascularized bone grafting (VBG), metaphyseal core decompression, and radial osteotomy, whereas the procedures performed on subjects in the late group included VBG, radial osteotomy, partial arthrodesis, proximal row carpectomy, tendon ball arthroplasty, and non-surgical treatment. These researchers found no statistically significant difference between any of the treatment groups for subjective pain outcomes. In terms of objective measures, statistically significant improvement (p < 0.05) was seen in range of motion after radial osteotomy and VBG in early-stage patients and after all interventions, except partial arthrodesis and non-surgical treatment, for late-stage patients. Grip strength was significantly improved in early-stage patients after radial osteotomy and VBG and for all late-stage patients, except among those managed non-surgically. Changes in Stahl and carpal height index scores were not statistically significant regardless of intervention, except after radial osteotomy in the early group, where they statistically worsened. The authors concluded that based on retrospective data from uncontrolled studies, no active treatment is superior in the treatment of Kienbock's disease and there are insufficient data to determine whether the outcomes of any intervention are superior to placebo or the natural history of the disease.
Chuong et al (1995) stated that deviations of the condylar form are usually ascribed to "degenerative arthritis" or "osteoarthritis". More recently, osteonecrosis has been discussed as a possible cause of condylar degeneration and pain. These researchers presented a review of the literature on osteonecrosis, emphasizing the spectrum of degenerative osseous disease, which includes osteoarthrosis, condylsis, osteomyelitis, and osteonecrosis. Preliminary results of mandibular core decompression with and without bone grafting were presented suggesting a therapeutic benefit. Moreover, the authors concluded that further study is needed to elucidate this process.
Lieberman et al (2014) stated that there is no consensus with respect to the best procedures to preserve the knee joint in patients with osteonecrosis of the knee. These investigators performed a systematic review of the literature between 1999 and 2012. Only 10 of 1,057 studies met inclusion criteria. Core decompression prevented additional surgical treatment in pre-collapse knees with a failure rate of 10.4 % (7 of 67 knees). Autogenous and osteochondral grafts decreased the need for additional surgery in both pre-collapse (0 %, 20 of 20) and post-collapse knees (10.5 %, 8 of 76 knees). The authors concluded that although these results are quite promising, multi-center randomized trials are needed to identify the optimal procedures to treat this disease.
Gross et al (2014) identified and summarized all available evidence for the treatment of talar AVN; provided treatment recommendations; and highlighted gaps in the literature. These investigators searched Medline and Embase using a unique algorithm. The Oxford Level of Evidence Guidelines and GRADE recommendations were used to rate the quality of evidence and to make treatment recommendations. A total of 19 studies fit the inclusion criteria constituting 321 ankles at final follow-up. The interventions of interest included hind-foot fusion, conservative measures, bone grafting, vascularized bone graft, core decompression, and talar replacement. All studies were Level IV evidence. Due to study quality, imprecise and sparse data, and potential for reporting bias, the quality of evidence is "very low". Studies investigating conservative therapy showed that prolonged protective weight-bearing provided the best outcomes in early talar AVN. The authors concluded that given the "very low" GRADE recommendation, understanding of talar AVN would be significantly altered by higher quality studies. Early talar AVN seems best treated with protected weight-bearing and possibly in combination with extracorporeal shock-wave therapy. If that fails, core decompression may be an attractive treatment option. Arthrodesis should be saved as a salvage procedure. Moreover, they stated that future prospective, randomized studies are needed to guide the conservative and surgical management of talar AVN.
In a Cochrane review, Marti-Carvajal et al (2014) determined the impact of any surgical procedure compared with other surgical interventions or non-surgical procedures, on AVN of bone in people with SCD in terms of safety and effectiveness. These investigators searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, comprising references identified from comprehensive electronic database searches and hand-searches of relevant journals and abstract books of conference proceedings. Additional trials were sought from the reference lists of papers identified by the search strategy. Date of the most recent search of the Group's Haemoglobinopathies Trials Register: March 17, 2014. Randomized clinical trials comparing specific therapies for AVN of bone in people with SCD were selected for analysis. Each author independently extracted data and assessed trial quality. Since only 1 trial was identified, meta-analysis was not possible. One trial (46 subjects) was eligible for inclusion. After randomization, 8 participants were withdrawn, mainly because they declined to participate in the trial. Data were analyzed for 38 participants at the end of the trial. After a mean follow-up of 3 years, hip core decompression and physical therapy did not show clinical improvement when compared with physical therapy alone using the score from the original trial (an improvement of 18.1 points for those treated with intervention therapy versus an improvement of 15.7 points with control therapy). There was no significant statistical difference between groups regarding major complications (hip pain, relative risk [RR] 0.95 (95 % confidence intervals [CI]: 0.56 to 1.60; vaso-occlusive crises, RR 1.14 (95 % CI: 0.72 to 1.80; very low quality of evidence); and acute chest syndrome, RR 1.06 (95 % CI: 0.44 to 2.56; very low quality of evidence)). This trial did not report results on mortality or quality of life. The authors found no evidence that adding hip core decompression to physical therapy achieved clinical improvement in people with SCD with AVN of bone compared to physical therapy alone. However, they highlighted that the conclusion was based on 1 trial with high attrition rates. They stated that further randomized controlled trials are needed to evaluate the role of hip-core depression for this clinical condition; end-points should focus on participants' subjective experience (e.g. quality of life and pain) as well as more objective “time-to-event” measures (e.g. mortality, survival, hip longevity).
Villa and colleagues (2016) reviewed the literature evaluating core decompression (CD) with BMMCs, CD alone, and bisphosphonate treatment in pre-collapse ONFH by focusing just on randomized controlled trials (RCTs) reporting functional and radiologic outcomes. These investigators determined if the literature provides evidence supporting any single approach. Using PubMed and Embase databases, these researchers reviewed the clinical evidence of treatments for pre-collapse ONFH following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines; 12 RCTs met the inclusion criteria. Results showed that CD with BMMCs had lower risk of femoral head collapse when compared to the CD alone excluding hips lost to follow-up (RR [95 % CI]: 0.25 [0.11 to 0.60]; p = 0.002) and when assumed that hips lost to follow-up experienced collapse (RR [95 % CI]: 0.11 [0.03 to 0.47]; p = 0.003). Neither CD nor bisphosphonate treatments showed lower risk to femoral head collapse when compared to control treatments (p = 0.46 and 0.31, respectively). The authors concluded that current literature showed that there is a lower risk of femoral head collapse in patients with ONFH treated with CD combined with BMMCs when compared to CD alone; however, there was no robust evidence to determine the effect on functional outcomes. They stated that more RCTs assessing new combination therapies and using standardized outcome measures are needed.
An UpToDate review on “Osteonecrosis (avascular necrosis of bone)” (Jones and Mont, 2017) states that “Core decompression for osteonecrosis of the shoulder has not been subjected to prospective, well-designed studies. A retrospective report describing core decompression of 95 shoulders with osteonecrosis reported “good to excellent clinical outcomes” in 74 (78 %) after a mean follow-up period of 6 years. Of those shoulders with Ficat and Arlet radiographic stage I, II, III, or IV osteonecrosis, symptomatic relief after decompression was noted in 94, 92, 71, and 13 %, respectively … In those with stage IV lesions and in those who have less severe radiographic disease but continued symptoms, total shoulder arthroplasty is the treatment of choice”.
Core Decompression for the Treatment of Post-Arthroscopic Osteonecrosis
Sargeant and colleagues (2019) stated that post-arthroscopic osteonecrosis is a rare complication that mostly occurs in individual over 50 years of age. It most commonly occurs in the medial femoral condyle, followed by the lateral femoral condyle then medial tibial plateau. These investigators reported the 1st case of lateral tibial plateau osteonecrosis in a young patient after arthroscopic lateral meniscectomy. This patient developed progressively deteriorating symptoms following uncomplicated arthroscopy; with a subsequent MRI showing bone edema and some overlying cartilage damage. Conservative measures were unsuccessful, so core decompression was undertaken. This has resulted in improved symptoms and subsequent follow-up MRI demonstrated resolution of edema with no progressive cartilage change. These investigators stated that post-arthroscopic osteonecrosis of the lateral tibial plateau is a rare condition with a poor outcome, usually resulting in arthroplasty. The authors concluded that the findings of this study suggested that core decompression may be successful in younger patients, however, larger studies with long-term follow-up are needed to confirm these preliminary findings, and that patients must be advised that this approach often leads to joint replacement surgery.
Adjunctive Treatments
Yu and associates (2015) reviewed the outcomes of using synthetic bone graft substitute (calcium sulfate and calcium phosphate) for the treatment of late-stage osteonecrosis of the femoral head. From November 2008 to May 2009, a total of 19 hips in 18 patients with osteonecrosis of the femoral head [6 hips in ARCO stage IIC and 13 hips in stage IIIA] were treated with core decompression combined with PRO-DENSE (injectable regenerative graft). The average age of the patients at the time of surgery was 48 years (range of 25 to 67 years); 12 patients (13 hips) overused alcohol, 4 patients (4 hips) were idiopathic, 1 patient (1 hip) used corticosteroids, and 1 patient (1 hip) was post-traumatic. The clinical failure was defined as conversion to total hip arthroplasty or progression in head collapse. At the conclusion of the study, 3 in the 6 stage IIC hips and 8 in the 13 stage IIIA hips were converted to total hip arthroplasty in an average of 8.5 months (range of 4 to 30 months) post-operatively. Advanced collapse of the femoral head awaiting for total hip arthroplasty was observed in the other 6 hips. Of the 19 hips, only 2 hips (10.5 %) survived without further collapse in the 5-year follow-up. This resulted in 89.5 % failure rate with early resorption of the grafting in an average of 5.3 months. The authors concluded that core decompression combined with an injectable calcium sulfate and calcium phosphate composite graft (PRO-DENSE) were associated high failure rates in the early post-operative period. They stated that this approach is not recommended for the treatment of ARCO stage IIC and IIIA osteonecrosis of the femoral head.
- how traditional core decompression is performed;
- adjunctive treatments;
- multiple percutaneous drilling techniques; and
- overall outcomes of these procedures.
Autologous Platelet Concentrate
Lopez-Jornet and colleagues (2016) performed a systematic literature review to determine the effectiveness of autologous platelet concentrate (APC) application, for prevention or treatment of medication-related osteonecrosis of the jaw (MRONJ) together with surgical debridement. An electronic search was performed using Medline (PubMed), Embase, and Cochrane databases until January 2015 using the following search terms: osteonecrosis, bisphosphonates, antiresorptive, antiangiogenic therapy, BRONJ, platelet concentrate, PRP, PRF, and PRGF. Two reviewers assessed the eligibility of articles independently and extracted key data. The methodology used met PRISMA criteria. The Newcastle-Ottawa scale was used to assess the quality of the articles. Preventive applications of PRP were reported in 697 dental extractions in patients taking bisphosphonates (BPs) intravenously, of whom 7 patients developed osteonecrosis (5 mandibular and 2 maxillary). In cases of established osteonecrosis, 8 studies reported treatment by surgery combined with APC (7 with PRP and 1 with leukocyte-rich and platelet-rich fibrin) in 123 patients (34 men and 89 women) with ONJ, who received 157 treatments, of which 135 achieved complete resolution (85.98 %). The authors concluded that there are no published scientific data to sufficiently support any specific treatment protocol, including the use of APC together with surgical debridement, for the management of MRONJ. They stated that RCTs of the use of APC are needed
Bisphosphonates and Mesenchymal Stem Cells (MSCs)
In a retrospective study, Gianakos et al (2016) examined if core decompression (CD) with mesenchymal stem cells combined with BP therapy can improve the clinical outcomes and reduce the risk of hip replacement when compared to treatment with BP therapy alone. Between 2006 and 2014, a total of 84 consecutive patients who were diagnosed with ONFH were identified from the authors’ institution's registry. Of these 84 patients, 49 patients (62 hips) fit inclusion/exclusion criteria; 29 patients (40 hips) were treated with BP therapy only; 20 patients (20 hips) were treated with BP, core decompression, and mesenchymal stem cells. Functional outcomes were assessed using the Modified Harris Hip Score (MHHS), the visual analog score (VAS), and evaluation of support system. Clinical failure was defined as deterioration of the MHHS/VAS scores and support system used severe enough to require THR. Radiologic outcome measures included the XR and MR imaging staging of the hip. Survival analysis was performed with total hip replacement as the end-point failure. Collapse was defined as progression from Ficat stage I or II to stage III and from Steinberg I, II, III to IV, V, VI. Failure requiring THR occurred in 21/40 (52.5 %) of BP-treated hips at a mean follow-up of 25.3 ± 11.5 months and 5/22 (22.73%) of BP + CD + MSC-treated hips at a mean follow-up of 22.7 ± 19.5 months. The median (Q1, Q3) time to collapse was 24.9 (7.4, 33.0) months in BP-treated hips and 27.3 (27.3) months in BP + CD + MSC-treated hips. There was no evidence of a difference in functional outcomes between the 2 treatment groups. After adjusting for baseline Ficat stage, age, and sex, an un-replaced hip treated with BP + CD + MSC had 0.42 (95 % CI: 0.11 to 1.57) times the risk of being replaced in the next moment compared to an un-replaced hip treated with BP only (p = 0.196). The authors concluded that these findings demonstrated that treatment with BP alone or BP + CD + MSC can postpone the need for total hip arthroplasty (THA) in the first 24 months in patients with ONFH compared to previously reported data, but there is no statistically significant difference between the 2 treatment groups. Combination therapy of BP + CD + MSC may be more effective in delaying the progression of collapse in early stage ONFH. Moreover, they stated that future prospective studies are needed to ascertain the effectiveness of these treatment strategies in the long-term.
Papakostidis and colleagues (2016) noted that the value of CD for treatment of ONFH is unclear. These researchers investigated by a literature review whether implantation of autologous bone marrow aspirate, containing high concentrations of pluripotent MSCs, into the CD track would improve the clinical and radiological results compared with the classical method of CD alone. The primary outcomes of interest were structural failure (collapse) of the femoral head and conversion to THR. All RCTs and non-RCTs comparing simple CD with autologous bone marrow cell implantation into the femoral head for the treatment of ONFH were considered eligible for inclusion. The methodological quality of the studies included was assessed independently by 2 reviewers using the Cochrane Collaboration tool for assessing risk of bias in randomized studies. Of 496 relevant citations identified, 7 studies formed the basis of this review. The pooled estimate of effect size for structural failure of the femoral head favored the cell therapy group, as, in this treatment group, the odds of progression of the femoral head to the collapse stage were reduced by a factor of 5 compared to the CD group (odds ratio [OR] = 0.2, 95 % CI: 0.08 to 0.6; p = 0.02). The respective summarized estimate of effect size yielded halved odds for conversion to THR in the cell therapy group compared to CD group (odds ratio [OR] = 0.6, 95 % CI: 0.3 to 1.02; p = 0.06). The authors concluded that these findings suggested that implantation of autologous MSCs into the core decompression track, particularly when employed at early (pre-collapse) stages of ONFH, would improve the survivorship of femoral heads and reduce the need for hip arthroplasty. Moreover, they stated that better designed RCTs with adequate sample sizes, based on power calculations, are needed to further determine the exact role of cytotherapy in the management of ONFH.
Bone Marrow Concentrate / Aspirate
In a prospective and randomized clinical trial, Pepke and associates (2016) examined the safety of injection of bone marrow aspirate concentrate during core decompression and studied its clinical (VAS; HHS) and radiological outcomes (MRI). These investigators evaluated 24 consecutive patients with non-traumatic femoral head necrosis (FHN) during a period of 2 years after intervention. In-vitro analysis of mesenchymal stem cells was performed by evaluating the fibroblast colony forming units (CFU-Fs). Post-operatively, significant decrease in pain associated with a functional benefit lasting was observed. However, there was no difference in the clinical outcome between the 2 study groups. Over the period of 2 years there was no significant difference between the head survival rate between both groups. In contrast to that, these researchers could not perceive any significant change in the volume of FHN in both treatment groups related to the longitudinal course after treating. The number of CFU showed a significant increase after centrifugation. The authors concluded that this trial could not detect a benefit from the additional injection of bone marrow concentrate with regard to bone regeneration and clinical outcome in the short-term.
Cabrolier and Molina (2016) noted that ONFH leads to degeneration of the head and finally to osteoarthritis of the hip. Decompression is the most widely used treatment, but its effectiveness is limited. These researchers stated that it has been proposed instillation of stem cells in addition to decompression, would lead to better results. Searching in Epistemonikos database, which is maintained by screening 30 databases, these investigators identified 2 systematic reviews including 2 randomized trials. They combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. The authors concluded that instillation of bone marrow stem cells at the time of core decompression probably slowed progression to osteoarthritis of the hip in patients with ONFH and might reduce the need of subsequent surgeries. However, they stated that it is unclear whether it has any effect on the functionality because the certainty of the evidence is very low.
Yuan and co-workers (2016) evaluated the clinical outcomes of ONFH after autologous bone marrow stem cell implantation. These investigators searched the PubMed, Embase and Web of Science databases and included all case-control trials that reported on the clinical outcomes of osteonecrosis progression, incidence of THA and improvement in HHS. Overall, 7 case-control trials were included. Compared with the controls, patients treated with the bone marrow stem cells implantation treatment showed improved clinical outcomes with delayed osteonecrosis progression (OR = 0.17, 95 % CI: 0.09 to 0.32; p < 0.001), a lower THA incidence (OR = 0.30, 95 % CI: 0.12 to 0.72; p < 0.01) and increased HHS (mean difference = 4.76, 95 % CI: 1.24 to 8.28; p < 0.01). The heterogeneity, publication bias, and sensitivity analyses showed no statistical difference significant differences between studies. The authors concluded that the findings of this study suggested that autologous bone marrow stem cells implantation has a good therapeutic effect on ONFH, resulting in beneficial clinical outcomes. However, they stated that trials with larger sample sizes are needed to confirm these findings.
Gangii and associates (2011) determined 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. These researchers studied 19 patients and 24 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. Bone marrow implantation afforded a significant reduction in pain and in joint symptoms and reduced the incidence of fractural stages. At 60 months, 8 of the 11 hips in the control group had deteriorated to the fractural stage whereas only 1 of the 13 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 2 groups at 60 months. Patients had only minor side-effects after the treatments. The authors concluded that 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. These investigators stated that larger studies are need to fully understand the results of this trial.
In a randomized control study, Sen and colleagues (2012) reported the findings of 51 osteonecrotic hips in 40 patients who were randomly divided into 2 treatment groups. Patients in group A (25 hips) were treated with core decompression, and those in group B (26 hips) received autologous bone marrow mononuclear cell instillation into the core tract after core decompression. Outcome between the 2 groups were compared clinically (Harris Hip score), radiographically (x-ray and magnetic resonance imaging [MRI]), and by Kaplan-Meier hip survival analysis after 12 and 24 months of surgical intervention. The clinical score and mean hip survival were significantly better in group B than in group A (p < 0.05). Patients with adverse prognostic features at initial presentation, that is, poor Harris Hip score, x-ray changes, edema, and/or effusion on MRI had significantly better clinical outcome and hip survival in group B than in group A. The authors concluded that further studies with larger sample size and longer follow-up are needed to establish the role of stem cell therapy in the treatment of osteonecrosis. This was a small study (n = 26 hips in the bone marrow mononuclear cell instillation group) with relatively short-term follow-up (up to 24 months).
Tabatabaee and co-workers (2015) stated that the management of early-stage osteonecrosis of the femoral head (ONFH) remains challenging. These researchers examined the effects of core decompression and concentrated bone marrow implantation on ONFH. The study recruited 28 hips with early ONFH randomly assigned into 2 groups of core decompression with (group A) and without (group B) bone marrow injection. Patients were evaluated using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire, visual analog scale (VAS) pain index, and MRI. The mean WOMAC and VAS scores in all patients improved significantly (p < 0.001); MRI showed a significant improvement in group A (p = 0.046) and significant worsening in group B (p < 0.001). The authors concluded that bone marrow stem cell injection with core decompression could be effective in early ONFH. These researchers stated that more studies with larger sample size and longer follow-up are needed to accept the role of stem cell therapy in the treatment of ONFH.
Hernandez and colleagues (2020) stated that untreated ONFH ultimately leads to secondary coxarthrosis. These researchers examined if the CD of the femoral head combined with implantation of autologous bone marrow concentrate with tricalcium phosphate could be used to prevent radiographic progression of early stage ON of the hip. They also examined if this approach would improve clinical outcomes and reduce the need THA. A total of 18 hips were included in the this trial. All of them underwent CD of the femoral head combined with implantation of autologous bone marrow concentrate with tricalcium phosphate between 2007 and 2012. The cell concentrate was obtained from the posterior iliac crest and processed and implanted during the same surgical procedure. Patient demographic data, clinical data including modified HHS, and radiological data were collected pre-operatively, post-operatively, and during the follow-up period. Furthermore, survival end-points were analyzed: time of femoral head collapse and need for THA. The mean age of patients was 37.8 years (SD, 9.31 years). The mean follow-up was 68.9 months (SD, 15.0 months). In most cases (70.6 %), the etiology of the ON of the femoral head was corticosteroid use; in the remaining cases, secondary to alcohol use. Core decompression of the femoral head combined with implantation of autologous bone marrow concentrate with tricalcium phosphate did not prevent progression to collapse (less than 80 % at 5 years) although mHHS improved. Overall median survival with the THA as end-point was 23 months (95 % CI: 14.9 to 31.1 months). Overall median survival time with any degree of collapse as end-point was 7 months (95 % CI: 2.0 to 12.0 months). The authors concluded that the findings of this study suggested that CD combined with implantation of autologous bone marrow concentrate and tricalcium phosphate would not prevent radiographic progression of early stage ON of the hip. These finding also suggested that the absence of indications for hip replacement alone was not an indicator of good response to the treatment, and it was important to note the radiological results.
Laser and Ozone Therapies
In a systematic review, Fliefe and colleagues (2015) evaluated the available treatments for bisphosphonate-related osteonecrosis of the jaws (BRONJ) and their outcomes. A literature search of PubMed, Cochrane Library, and Web of Science databases was conducted in accordance with the PRISMA statement, search phrases were “jaw osteonecrosis” OR “bisphosphonate-related osteonecrosis” OR “bisphosphonate osteonecrosis” AND “treatment” OR “outcomes”. A total of 97 articles published between 2003 and February 2014 were reviewed. The studies reported 4,879 cases of BRONJ. The mean age of the patients was 66.5 ± 4.7 years. The male to female ratio was 1:2. The mean duration of BP administration was 38.2 ± 15.7 months. The quality of the publications was good, with some moderate and poor. Minimally invasive surgical treatment was the treatment most used. Medical treatment was also used. Adjunctive treatments included laser, growth factors, hyperbaric oxygen and ozone. The authors concluded that the articles provided a broad range of outcome variables to assess the treatment of BRONJ and the outcomes of each treatment; considerable heterogeneity was found regarding study design, sample size, and treatment modalities. They stated that clinical trials with larger samples are needed to provide sufficient information for each treatment modality to predict the outcomes of each treatment.
Latifyan et al (2016) noted that ONJ resulting from administration of BP or denosumab is a rare but severe complication in cancer patients. Complete remission depends on the stage of ONJ; it can be estimated in the range of 20 to 30 %. Low-level laser therapy (LLLT) has been advocated as a logical additional option; LLLT irradiation has anti-inflammatory actions and thus can help to control pain, as well as bio-stimulating properties with favorable actions on bacterial control and wound healing. These investigators reviewed the results of 7 published studies of LLLT in BP-associated ONJ; LLLT resulted in an overall response rate of 55 % superior to that observed in controls (30 %). The findings suggested that there might be an advantage to add LLLT to the "classical" management of ONJ. The authors concluded that further research is needed to remove any doubt of protection or enhancement of carcinogenic processes; they believe that prospective well-controlled studies of LLLT in ONJ are needed. If the positive results are confirmed, it would represent a great improvement for the quality of life of many patients.
Platelet-Rich Fibrin (PRF)
Gonen and Yılmaz Asan (2017) stated that platelet-rich fibrin (PRF) is a second generation platelet concentrate, and has the ability of regulating the inflammation and stimulation of chemotactic agents. These researchers presented the treatment of stage-III BRONJ by PRF. A 77-year old male patient with stage-III BRONJ was treated with minimal surgical operations and PRF membrane. The patient was followed-up for 18 months, and there was no recurrence or exposure. The authors concluded that PRF may promote the healing of both bone and soft tissues even in stage-III patients. They stated that this technique is an alternative treatment modality for the closure of bone exposure and tissue healing in BRONJ patients. The findings of this sing-case study need to be validated by well-designed studies.
Norholt and Hartlev (2016) evaluated the outcome of the surgical treatment of osteonecrosis of the jaw (ONJ) with the additional use of autologous membranes of PRF. The study population consisted of 15 patients with ONJ lesions in the maxilla (n = 3), mandible (n = 11), or both (n = 1); 8 patients had malignant disease and were treated with high-dose anti-resorptive medication; 7 were treated with low-dose anti-resorptive drugs for osteoporosis; 13 patients had grade 2 ONJ lesions and 2 had grade 3 lesions. The following standardized surgical technique was applied: resection of necrotic bone, mobilization of mucoperiosteal flaps, and multiple layer coverage of bone with PRF membranes. At follow-up of 7 to 20 months after surgery, complete mucosal healing and an absence of symptoms were found in 14 of the 15 patients (93 %). The patient with persistent bone exposure had a grade 3 ONJ lesion before surgery. The authors concluded that the findings of this study suggested that the use of PRF membranes in the surgical treatment of grade 2 ONJ may be a contributing factor to a successful outcome. These preliminary findings need to be further investigated.
Bone Morphogenic Proteins
Pan and co-workers (2014) examined the effect of recombinant human bone morphogenetic protein 2/poly-lactide-co-glycolic acid (rhBMP-2/PLGA) with core decompression on repair of rabbit femoral head necrosis. Bilateral femoral head necrosis models of rabbit were established by steroid injection. A total of 48 rabbits (96 femoral head necrosis) were randomly divided into 4 groups: Group A, control group with 12 rabbits, 24 femoral head necrosis; Group B, treated with rhBMP-2/PLGA implantation after core depression, with 12 rabbits, 24 femoral head necrosis; Group C, treated with rhBMP-2 implantation after core depression, with 12 rabbits, 24 femoral head necrosis; and Group D treated with core depression group without implantation, with 12 rabbits, 24 femoral head necrosis. All animals were sacrificed after 12 weeks. The ability of repairing bone defect was evaluated by X-ray radiograph. Bone mineral density analysis of the defect regions were used to evaluate the level of ossification. The morphologic change and bone formation was assessed by hematoxylin and eosin (HE) staining. The angiogenesis was evaluated by vascular endothelial growth factor (VEGF) immunohistochemistry. The osteogenetic ability and quality of femoral head necrosis in group B were better than those of other groups after 12 weeks by X-ray radiograph and morphologic investigation. And the angiogenesis in group B was better than other groups. Group C had similar osteogenetic quality of femoral head necrosis and angiogenesis with group D. The authors concluded that the treatment of rhBMP-2/PLGA implantation after core depression can promote the repair of rabbit femoral head necrosis. They noted that it is a promising and efficient synthetic bone material to treat the femoral head necrosis.
- LPFH and
- non-LPFH groups.
The authors stated that this study had several drawbacks. It was limited by virtue of the retrospective analysis. Because osteonecrosis after femoral neck fractures is relatively uncommon in children and adolescents, it would have been difficult to mount a RCT. The sample size of this study was relatively small (n = 51). Due to the limited number of cases, it was believed that the cell transplantation plus BMP-2 enhanced the success rate of CD compared with other researches, which should be further confirmed by future high-quality, multi-center case-control studies. Considering the impact of the radiation, the CT scan was not used in regular follow-up, which may influence the radiological observation of the state of osteogenesis. They stated that despite these limitations, however, it was considered that this retrospective study might be valuable to clarify a hypothesis, provided an available method, and focus on the study question.
Parathyroid Hormone[1-34] (PTH[1-34])
Zhou and colleagues (2017) noted that steroid-associated osteonecrosis (SAON) might induce bone collapse and subsequently lead to joint arthroplasty. Core decompression is regarded as an effective therapy for early-stage SAON, but the prognosis is unsatisfactory due to incomplete bone repair. Parathyroid hormone[1-34] (PTH[1-34]) has demonstrated positive efficacy in promoting bone formation. These researchers evaluated the effects of PTH on improving the effects of CD in early-stage SAON. Distal femoral CD was performed 2 weeks after osteonecrosis induction or vehicle injection, with 10 of the ON-induced rabbits being subjected to 6-week PTH[1-34] treatment and the others, including ON-induced and non-induced rabbits, being treated with vehicle; MRI confirmed that intermittent PTH administration improved SAON after CD therapy. Micro-CT showed increased bone formation within the tunnel. Bone repair was enhanced with decreased empty osteocyte lacunae and necrosis foci area, resulting in enhanced peak load and stiffness of the tunnel. Additionally, PTH enlarged the mean diameter of vessels in the marrow and increased the number of vessels within the tunnels, as well as elevated the expression of BMP-2, RUNX2, IGF-1, bFGF and VEGF, together with serum OCN and VEGF levels. The authors concluded that PTH[1-34] enhanced the effectiveness of CD on osteogenesis and neovascularization, thus promoting bone and blood vessels repair in the SAON model. They stated that these results might provide a potential therapeutic strategy for patients with early-stage SAON. These preliminary findings need to be further investigated in well-designed studies.
Synthetic Bone Graft Substitute (e.g., Calcium Sulphate and Calcium Phosphate)
Landgraeber and colleagues 920170 stated that advanced core decompression (ACD) is a new technique for treatment of ONFH that includes removal of the necrotic tissue using a percutaneous expandable reamer followed by refilling of the drill hole and the defect with an injectable, hard-setting, composite calcium sulphate (CaSO4)-calcium phosphate (CaPO4) bone graft substitute. As autologous bone has been shown to be superior to all other types of bone grafts, the aim of the study was to present and evaluate a modified technique of ACD with impaction of autologous bone derived from the femoral neck into the necrotic defect. A cohort of patients with an average follow-up of 30.06 months (minimum of 12 months) was evaluated for potential collapse of the femoral head and any reasons that led to replacement of the operated hip. Only patients in stages 2a to 2c according to the Steinberg classification were included in the study. In 75.9 % the treatment was successful with no collapse of the femoral head or conversion to a THR. Analysis of the results of the different subgroups showed that the success rate was 100 %, 84.6 % and 61.5 % for stages 2a, 2b and 2c lesions, respectively. The authors concluded that previous studies with a comparable follow-up reported less favorable results for ACD without autologous bone. Especially in stages 2b and 2c the additional use of autologous bone had a positive effect. They stated that in comparison to other hip-preserving techniques, the modified ACD technique is a very promising and minimally invasive method for treatment of ONFH. These researchers noted that even if it is still too early to draw final conclusions, the modified technique of ACD appeared to be superior to the previous one; further long-term follow-up is needed to receive final assurance.
Autologous Stem Cells / Bone Marrow Stem Cells
Xu and co-workers (2017) evaluated the safety and efficacy of CD combined transplantation of autologous bone marrow stem cells (CDBMSCs) for treatment of avascular necrosis of the femoral head (ANFH); RCTs regarding effectiveness of CDBMSCs for treating ANFH were searched in 8 comprehensive databases prior to September 2016. The data analysis was performed by using the RevMan version 5.3. A total of 11 studies with 507 participants were included. Results showed that CDBMSCs group was more effective than CD group in increasing HHS, decreasing necrotic area of femoral head, collapse of femoral head, and conversion to THR incidence. In the subgroup analysis, the results did not change in different intervention measure substantially. In addition, the safety of CDBMSCs for ANFH was reliable. The authors concluded that this systematic review found that BMSCs implantation into the CD track appeared to be more effective in the treatment of ANFH than CD only, delayed ANFH progression, reduced necrotic area of femoral head, decreased the need for THA, and improved HHS. However, they stated that more rigorously designed and higher quality trials with larger sample size are needed for confirming the effectiveness of CD combined with BMSCs on ANFH.
The authors stated that this study had several drawbacks that should be taken into consideration when accepting the findings of this review. First, the vast majority of the included trials failed to describe detailed information about randomization, allocation concealment, and blinding, as these are the core standards of a well-designed RCT. It was hard to randomly allocate the patients' hip joint that most of clinical studies failed to randomize. These reasons contributed to risk of bias of included studies. Second, all trials reported positive effects in the CDBMSCs for the treatment of ANFH, while negative findings were less likely to be published, implying that publication bias may have existed. Third, except for 1 study, the remainder of the studies ignored the sample size estimation. All included studies were of small sample sizes, which weakened the validity of statistical analysis. Lastly, these investigators failed to generate a funnel plot for outcomes to detect potential publication bias due to the limited number of included trials.
Li and associates (2020) noted that ANFH is a severely disabling disease of the hip. Several clinical trials have shown promising outcomes on the use of mesenchymal stem cells for the treatment of ANFH, but long-term clinical assessments are lacking. Previously, these researchers reported the 2-year follow-up results of a prospective, double-blinded RCT on autologous bone marrow buffy coat grafting combined with CD in patients with ANFH. In this study, these investigators reported the 10-year follow-up results. They recruited 43 (53 hips) patients from 2009 to 2010. The hips were randomly allocated to CD with or without bone marrow buffy coat (BBC) grafting. Subjects underwent follow-up at 24, 60, and 120 months post-operatively. The VAS, Lequesne algo-functional index, and WOMAC osteoarthritis (OA) scores were recorded. Survival rate analysis and prognostic factor analysis were performed. The end-point was defined as progression to Ficat stage IV or conversion to THA. A total of 31 patients (41 hips) were included in the final analysis. The CD + BBC group had better subjective assessment scores than the CD group. The average survival times were 102.3 months and 78.1 months in the CD + BBC group and CD group, respectively (log-rank test, p = 0.029). In the univariate Cox proportional hazards regression model, age [hazard ratio (HR) = 1.079, p = 0.047] and pre-operative Ficat stage (HR = 3.283, p = 0.028) indicated a high risk for progression, while the use of BBC (HR = 0.332, p = 0.042) indicated a low risk. Pre-operative Ficat stage III was isolated as an independent risk factor for clinical failure in the multi-variate model (HR = 3.743, p = 0.018). The authors concluded that the 10-year follow-up results of this prospective, double-blinded RCT showed that the use of autologous BBC in combination with CD was more effective than the use of CD alone.
The authors stated that this study had some drawbacks. First, as mentioned above, the number of patients included in the final analysis was small, so these researchers did not perform subgroup analysis with respect to etiology. Second, they included patients with bilateral ANFH, so the potentially similar performance of the bilateral hips may have led to a contralateral effect related to cell therapy. Third, these investigators did not obtain MRI images post-operatively, which interfered with the accuracy of staging. Last but not least, there was a lack of evidence of the fate and track of the implanted cells, thus, the use of a cell-labelling technique would be beneficial.
In a meta-analysis, Wang and colleagues (2020) examined the safety and effectiveness of BMSCs with CD for ONFH based on RCTs. Electronic database of PubMed, Embase, Google Scholar, China National Knowledge Infrastructure (CNKI), and Wanfang database was searched up to December 26, 2019 for relevant RCTs about combined utilization of BMSCs and CD versus CD alone for ONFH. Gray literature sources were also searched. These researchers conducted a meta-analysis following the guidelines of the Cochrane Reviewer's Handbook; 2 independent reviewers performed the data extraction and assessed study quality. Outcomes included the HHS at 12 months, HHS at 24 months, necrotic area of femoral head, conversion to THA, VAS at final follow-up, and adverse effects. The meta-analysis was performed with Stata 12.0. A total of 15 published studies with 688 patients fulfilled the requirements of inclusion criteria. Across all populations, subjects in combined utilization of BMSCs group showed a statistical significance with higher HHS at 12 months (standard mean difference [SMD] 0.53, 95 % CI: 0.29 to 0.77) and 24 months (SMD 0.57, 95 % CI: 0.36 to 0.77). Similarly, subjects in combined utilization of BMSCs group had more advantages in reducing necrotic area of femoral head (SMD -1.05, 95 % CI: -1.73 to -0.38) and the rate of conversion to THA (RR = 0.53, 95 % CI: 0.38 to 0.74, p = 0.000). No significant differences were identified regarding adverse effects postoperatively (RR = 1.03, 95 % CI: 0.64 to 1.67, p = 0.893). The authors concluded that compared with CD treated alone in the treatment of ONFH, combined utilization of CD and autologous BMSCs implantation had a better pain relief and clinical outcomes and could delay the collapse of the femoral head more effectively. However, these researchers stated that more rigorously designed and higher RCTs with larger sample size are needed for better confirming the effectiveness of combined utilization of BMSCs and CD on ONFH.
The authors stated that this meta-analysis had several drawbacks. The number of subjects was small, thus, larger-scale clinical trials were needed. Meanwhile, the BMSCs isolated, collected and number administrated in each study were differed from each other, which would bias the findings. Finally, due to the lack of long follow-up, it was difficult to determine the status of the ONFH treated by these 2 strategies at a time-point of greater than 2 years, therefore, trials with longer follow-up should be performed in the future.
Zhang and co-workers (2020) examined the evidence on the effect of adjuvant BMSCs for early stage ONFH. These researchers carried out a systematic review of the Medline, PubMed, Embase, and Cochrane data-bases in search of published reports comparing the CD with/without adjuvant BMSCs for ONFH. The cohort was divided into 2 groups: CD with BMSCs (intervention), and CD alone (control subject). The various outcome parameters including hip pain and function, progression of ONFH, rate of revision surgeries, and complications were analyzed. Data were extracted and aggregated for meta-analysis. Cases with staging beyond Ficat II, UPENN II, or ARCO II were excluded. Of the published reports, 16 met inclusion criteria with an aggregated 583 hips in the intervention and 468 hips in the control subject groups, respectively. Addition of bone marrow cells to CD resulted in lower hip pain score (VAS) (MD = -10.88, 95 % CI: -16.84 to -4.92, p = 0.003) and higher HHS score (MD = 5.59, 95 % CI: 1.13 to 10.04, p = 0.01) compared with CD alone at the 24-month follow-up. For rates of progression to higher stages, 138 progressed in the intervention group compared with 202 in the control subject group (p = 0.0002). Finally, subsequent patients who required THA were lower in the intervention group (22.5 % versus 42.3 %, p = 0.001). The authors concluded that despite heterogeneous and poor data, there is evidence that addition of bone marrow cells to CD appeared to result in better clinical outcomes and lower rates of disease progression compared with cored decompression alone. Level of Evidence = III. These findings need to be validated by well-designed studies.
Zhu et al (2021) stated that the value of CD in the treatment of ONFH remains controversial. In a systematic review and meta-analysis, these investigators examined if CD combined with other treatments could improve the clinical and radiological outcomes of ONFH patients compared with CD alone. They searched the PubMed, Embase, Web of Science, and Cochrane Library databases until June 2020. All RCTs and clinical controlled trials (CCTs) comparing CD alone, and CD combined with other measures (CD + cell therapy, CD + bone grafting, CD + porous tantalum rod, etc.) for the treatment of ONFH were considered eligible for inclusion. The primary outcomes of interest were HHS, ONFH stage progression, structural failure (collapse) of the femoral head, and conversion to THA. The pooled data were analyzed using Review Manager 5.3 software. A total of 20 studies with 2,123 hips were included (CD alone = 768, CD combined with other treatments = 1,355). The combination of CD with other therapeutic interventions resulted in a higher HHS (mean difference (MD) = 6.46, 95 % CI: 2.10 to 10.83, p = 0.004) and WOMAC score (MD = -10.92, 95 % CI: -21.41 to -4.03, p = 0.040) and a lower VAS score (MD = -0.99, 95 % CI: -1.56 to -0.42, p < 0.001) than CD alone. For the rates of disease stage progression, 91 (20 %) progressed in the intervention group compared to 146 (36 %) in the control group (OR = 0.32, 95 % CI: 0.16 to 0.64, p = 0.001). Furthermore, the intervention group had a more significant advantage in delaying femoral head progression to the collapsed stage (OR = 0.32, 95 % CI: 0.17 to 0.61, p < 0.001) and reducing the odds of conversion to THA (OR = 0.35, 95 % CI: 0.23 to 0.55, p < 0.001) compared to the control group. There were no serious adverse events (AEs) in either group. Subgroup analysis showed that the addition of cell therapy significantly improved clinical and radiological outcomes compared to CD alone, and this approach appeared to be more effective than other therapies, especially in pre-collapse (stage I to II) ONFH patients. The authors concluded that there was marked heterogeneity in the studies. There was a trend towards improved clinical outcomes with the addition of stem cell therapy to CD. Moreover, these researchers stated that more rigorously designed and higher-quality prospective and randomized trials with adequate sample sizes are needed to confirm the effectiveness of cell therapy and other treatment measures in the management of ONFH.
The authors stated that this meta-analysis had several drawbacks. First, the overall quality of the evidence was heterogeneous and poor, and included trials that failed to detail information regarding randomization, allocation concealment, and blinding. These omissions contributed to bias. Second, although these investigators performed subgroup analyses of different methods and different stages of ONFH, different etiologies of ONFH may also have posed risks for bias. Third, although these researchers carried out a subgroup analysis to examine if the addition of cell therapy would achieve better clinical and radiological outcomes than CD alone, the processing, quality, and number of stem cells harvested for implantation were not standardized; therefore, adding to the heterogeneity of the data. Fourth, different classification systems for ONFH were used in studies (Ficat and Arlet; Association Research Circulation Osseous (ARCO); Steinberg), which may have affected the final meta-analysis results to some extent. Furthermore, several recent studies have reported that Japanese Investigation Committee (JIC) classification based on the size and location of ONFH lesions involving the acetabular head may provide better assistance in the selection of treatment for femoral head necrosis. This of course requires further research. Fifth, although these researchers carried out the subgroup analysis and sensitivity analysis, there was still heterogeneity in some outcome indicators. This may have affected the final decision of orthopedic surgeons, although the results of a statistical test did not indicate otherwise. Finally, the sample size was small in some of the trials, which weakened validity of the statistical analysis and may have over-estimated the therapeutic effects of certain methods. Thus, these investigators stated that one should be cautious regarding the results of the meta-analysis.
In a systematic review and meta-analysis, Li et al (2021) examined if stem cell combination therapy is superior to single CD or porous tantalum rod implantation in the treatment of ONFH. These investigators carried out a systematic search of the literature to examine all included RCTs on stem cell combination therapy for patients with ONFH in PubMed, Cochrane Library, Web of Science, and Embase sites. They evaluated the quality and risk of bias for the included studies. And the outcomes of HHS, VAS, and AEs were statistically analyzed. These researchers included 10 RCTs (498 patients with 719 hips). Stem cell therapy combined with CD versus CD alone for HHS of ONFH was different (MD = 8.87, 95 % CI: 5.53 to 12.22], p < 0.00001). The combination of stem cell therapy and CD could effectively improve HHS. Similarly, the VAS of the stem cell combination therapy group also differed compared with the control group (MD = -14.07, 95 % CI: -18.32 to -9.82, p < 0.00001). The result showed that stem cell combination therapy could relieve the pain of patients with ONFH . There was no significant difference in AEs between the combination therapy group and the control group (RR = 1.57, 95 % CI: 0.62 to 3.97, p = 0.34). The authors concluded that stem cell therapy combined with CD was a feasible and effective method with few complications in the clinical treatment of early-stage ONFH. Even in the combination of porous tantalum rod implantation and peripheral blood stem cells, stem cell combination therapy was superior to single biomechanical support treatment. Moreover, these researchers stated that high-quality, large-sample, multi-center, and long-term follow-up RCTs are still needed to corroborate the safety and effectiveness of stem cell combination therapy in ONFH treatment.
The authors stated that the findings of this meta-analysis had several drawbacks. First, the overall quality of the scope of included literature was not high, the sample size was small, and the short-term follow-up time in some studies may have led to potential bias. Second, as no more than 10 studies were included, publication bias could not be examined. Third, publication in English may have resulted in language or regional bias. Fourth, there was some heterogeneity in outcome indicators.
Bone Grafting
Yoon and colleagues (2018) stated that CD has been used to treat early-stage (pre-collapse) ONFH in an attempt to prevent collapse. Recently, other adjunctive treatments including bone grafting (BG) and bone marrow mononuclear cells (BMMC) were combined to traditional CD to improve the results. These investigators examined the efficacy of various CD modalities and non-operative treatment through a network meta-analysis (NMA). A total of 9 RCTs with a minimum 2 year follow-up were retrieved from PubMed, Embase, and Cochrane Library search. Treatment modalities were categorized into 5: traditional CD alone, CD combining BG, CD combining BMMC, CD combining BG and BMMC, and non-operative treatment. The rate of conversion to THA and the radiologic progression were compared among the 5 treatments. A total of 453 hips were included in the NMA; 151 hips in CD, 70 hips in CD combining BG, 116 hips in CD combining BMMC, 25 hips in CD combining BG and BMMC, and 91 hips in non-operative treatment. There were no differences in the rate of THA conversion across all 5 treatment modalities. The pooled risk ratio compared with non-operative treatment for THA conversion was 0.92 (95 % CI: 0.19 to 4.43; p = 0.915) in traditional CD; 4.10 (95 % CI: 0.37 to 45.42; p = 0.250) in CD combining BG; 0.30 (95 % CI: 0.04 to 2.49; p = 0.267) in CD combining BMMC; and 1.78 (95 % CI: 0.05 to 63.34; p = 0.750) in CD combining BG and BMMC. No significant differences were found in terms of the radiologic progression across all treatments. The authors concluded that in the current NMA, they did not find any differences in the rates of THA conversion and radiologic progression across all CD modalities and non-operative treatment. They stated that these findings question the assumption that CD changes the natural course of ONFH. Considering that size of necrotic portion was the major determinant of future collapse of the necrotic femoral head and the collapse did not occur in small lesions even without any treatment, a large-scale RCT is needed to confirm the effectiveness of CD.
Extracorporeal Shockwave
Qiao and colleagues (2020) noted that previous studies have reported that combined extracorporeal shockwave (EPSW) with spinal CD (SCD) has been used for the treatment of patients with femoral head necrosis (FHN) effectively. However, their results are still inconsistent. Thus, this study will systematically examine the safety and efficacy of EPSW and SCD for the treatment of patients with FHN. This study will systematically search the following data-bases from inception through March 1, 2020: Medline, Web of Science, Scopus, Embase, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, and China National Knowledge Infrastructure. All searches will be performed without language and publication date restrictions. This study will only include RCTs examining the safety and efficacy of EPSW and SCD for the treatment of patients with FHN. Two authors will independently evaluate all literatures, extract data, and appraise risk of bias. Any disagreement between 2 authors will be resolved by a 3rd author through discussion. RevMan 5.3 software will be utilized to analyze the data and to perform a meta-analysis if necessary. This study will summarize up-to-date evidence and provide a detailed summary related to the safety and efficacy of EPSW and SCD for the treatment of patients with FHN. The authors concluded that this study may provide helpful evidence to determine whether or not EPSW combined SCD is safe and effective for the treatment of patients with FHN. It will also provide reference and recommendation for clinical practice and future studies.
Zhang, et al. (2017) conducted an electronic database search using PubMed, Embase, and the Cochrane library to collect clinical trials, case reports, and cases series on the use of extracorporeal shock wave in osteonecrosis of the femoral head, and then useful data were extracted and appraised by experienced clinicians. The authors evaluated the quality of included evidences by using the Oxford Centre for evidence-based medicine (EBM) Levels of Evidence. A total of 17 articles including 2 case reports, 9 open label trials, 2 cohorts, and 6 randomized controlled trials were considered to be eligible for this systematic review. Visual analog scale (VAS), Harris hip scores, and the imaging results were the frequently-used outcome estimates of included studies. By systematically analyzing this evidence, the authors concluded that ESWT could act as a safe and effective method to improve the motor function and relieve the pain of patients with osteonecrosis of femoral hip, especially those at early stage. Imaging revealed that bone marrow edema was significantly relieved, but the necrotic bone could not be reversed after ESWT. This technique could slow or even block the progression of ONFH and therefore reduce the demand for surgery. Collaboration with other conservative modalities would not improve the curative benefits of ESWT. Meanwhile, ONFH with various risk factors showed similar reaction to this noninvasive treatment method. The authors stated, however, that these conclusions should be interpreted carefully for the low-quality of included publications and further studies are requisite to validate the effect of ESWT in ONFH.
Platelet-rich Plasma Combined with Stem Cells
Houdek and colleagues (2018) reported the results in a preliminary series of patients with ONFH treated with PRP plus bone marrow-derived mesenchymal stem cells (BmMSCs). A total of 22 consecutive patients (35 hips; 11 men and 11 women) with corticosteroid-induced osteonecrosis who met study inclusion criteria were enrolled; none declined participation, and none was lost to follow-up, although 1 patient (2 hips) died within a year of the procedure for reasons unrelated to it, and 5 patients (7 hips) did not undergo MRI at the 1-year follow-up. All patients had pre-collapse osteonecrosis, rated either University of Pennsylvania Stage 1 (n = 4) or Stage 2 (n = 31 hips). Mean age and body mass index (BMI) were 43 years and 31 kg/m, respectively. Patients underwent pre- and post-operative radiography and MRI to assess femoral head involvement using the modified Kerboul angle. Absolute cell count and colony-forming unit (CFU) assays were used to assess MSC abundance and viability of the bone marrow obtained at the time of surgery. Patients were followed at regular intervals to assess clinical response to treatment with a mean follow-up of 3 years (range of 2 to 4 years). The change in femoral head involvement was assessed with the modified Kerboul angle; the HHS was used to assess clinical outcome; and conversion to THA, re-operation, and survivorship free from femoral head collapse were analyzed with the Kaplan-Meier method on a per-hip basis. Survivorship free from THA, any procedure, and femoral head collapse was 84 % (95 % CI: 75 % to 93 %), 67 % (95 % CI: 55 % to 79 %), and 93 % (95 % CI: 76 % to 98 %), respectively, at 3 years post-operatively; 2 patients (4 hips) underwent a 2nd decompression and MSC injection for persistent pain without signs of radiographic collapse. All patients with collapse underwent THA. The mean modified Kerboul angle improved from 205° ± 47° to 172° ± 48° post-operatively (mean change of -30° ± 6°, p = 0.01). A greater proportion of patients who underwent an additional procedure had a modified Kerboul grade of 3 or 4 pre-operatively (80 % [4 of 5] versus 13 % [4 of 30 Grade 1 or 2; OR, 26; 95 % CI: 2 to 296; p = 0.005). Pre-operatively the mean HHS was 57 ± 12, which improved to 85 ± 15 (mean change of 28 ± 3, p < 0.001) at most recent follow-up. Patients undergoing a re-operation or THA had a lower mean concentration of nucleated cells/ml (5.5 x 10 ± 2.8 x 10 cells/mL versus 2.3 x 10 ± 2.2 x 10 cells/ml, p = 0.02) and lower mean CFUs (13 ± 6 versus 19 ± 7, p = 0.04) compared with those who did not. The authors concluded that core hip decompression with injection of PRP plus concentrated bone marrow improved pain and function; greater than 90 % of hips in this series were without collapse at a minimum of 2 years. They stated that in this preliminary study, successful results were seen when nucleated cell count was high and modified Kerboul grade was low. Moreover, these researchers stated that further randomized studies are needed to determine this procedure's efficacy versus core decompression or non-operative treatment alone.
Platelet-Rich Plasma Combined with Mesenchymal Stem Cells, and Synthetic Bone Graft
D'Ambrosi and colleagues (2018) reported the rate of survivorship in patients with ONFH treated with CD in association with MSCs implantation, PRP injection, and synthetic bone graft. These researchers evaluated 24 hips in 16 patients, according to Ficat classification, treated by CD, injection of PRP and MSCs, and back-filling of the core tract with synthetic bone graft. Survivorship was estimated using Kaplan-Meier curves. The survivorship of CD in association with the procedure was 50 % at 75 months of follow-up. The survival rate was 80 % for patients in early stage and 28.6 % for patients in advanced stage at 75 months. When these investigators compared Kaplan-Meier survival curves of patients in stage III + IV and patients in stage I + II, they noticed that the survival functions were statistically different (p < 0.05, log-rank test), particularly in stage I + II where we had a greater surviving core decompression, in comparison to patients in stage III + IV. The authors concluded that these findings suggested that the technique was safe and good preliminary results were obtained in patients with early stages of the disease with no reported complications.
The authors stated that this study had 2 main drawbacks. First, small number of patients (n = 16). Second, these researchers mixed 4 different techniques (core decompression, PRP, MSCs, and synthetic bone graft); thus, it was impossible to clearly know which of the procedures was truly effective in improving outcomes.
Hyperbaric Oxygen Therapy in Femoral Head Necrosis
Paderno and colleagues (2021) stated that although many studies have shown that hyperbaric oxygen therapy (HBOT) can significantly improve symptoms and quality of life (QOL) of patients affected by FHN, this therapy is not worldwide approved yet. In a meta-analysis, these researchers examined the effect of HBOT in the treatment of FHN. Relevant studies published before May 2020 were systematically searched using terms related to HBO and FHN. Fixed and random-effects models were used to estimate the OR with 95 % CI. Subgroup analyses and publication bias tests were performed to examine potential study heterogeneity and bias. A total of 10 studies involving 353 controls and 368 HBOT-treated cases were included, most of which were conducted on Asian population. The clinical effect in the HBOT group was 3.84 times higher than in the control group (OR = 3.84, 95 % CI: 2.10 to 7.02, p < 0.00001). Subgroup analyses showed that the clinical effect of HBOT was statistically significant in the Asian subpopulation that represented most of the subjects (OR = 3.53, 95 % CI: 1.87 to 6.64, p < 0.00001), but not in the non-Asian subpopulation, probably because of insufficient numerosity (OR = 7.41, 95 % CI: 0.73 to 75.71, p = 0.09). The authors concluded that the findings of this meta-analysis suggested that patients with FHN treated with HBOT can achieve a significant clinical improvement.
The authors stated that the drawbacks of this meta-analysis derived mostly from the constraints imposed by the quantity and quality of research. It is necessary to perform a large RCT in the future. Therefore, this work suggested that future clinical trials should pay attention to several aspects and hypothesized needs for better evidence:
- Design a standard for defining the most proper characteristics in patients’ selection (age, race, BMI, clinical and pharmacological history, stage of FHN by a unique method of classification, unilateral or bilateral hips involved, use or not of crutch suitable, smoke or not);
- Standardize the HBO dives for the proposed indication (ATA, time, number of treatments);
- Define and standardize the best follow-up protocol to adopt;
- Adopt a shared standard for data presentation (number of the hips treated and not of patients);
- Long-term timing in the study follow-up to facilitate observation of the endpoint to draw a positive conclusion.
Surgery for Humeral Head Avascular Necrosis in Patients with Sickle Cell Disease
Alkhateeb and colleagues (2021) noted that sickle-cell disease (SCD) is the leading etiology for atraumatic humeral head AVN (HHAVN) worldwide. Treatment of HHAVN is not standardized, with only few studies examining clinical outcomes following surgical interventions. In a systematic review, these investigators examined the available evidence on the results of surgery for HHAVN in the SCD population. They carried out an electronic search using PubMed (Medline), Embase, and Cochrane Library databases. Relevant studies that reported the outcomes of surgical intervention for HHAVN for patients with SCD were reviewed. Outcome parameters were pain, range of motion (ROM), specific shoulder outcome scores, and complications. A total of 6 studies, 3 retrospective cohorts (2 level III and 1 level IV) and 3 case series (level IV), were included in this review. A total of 43 patients with SCD, comprising 49 shoulders, underwent different surgical procedures. Surgical procedures were core decompression, arthroscopic intervention, humeral head re-surfacing, shoulder hemiarthroplasty, and total shoulder arthroplasty (TSA). The authors concluded that considering the low level of evidence of included articles in this review, there is a urgent need for larger, high-quality, prospective and comparative studies to further examine the effectiveness of surgery in treating humeral head osteonecrosis in the SCD population. For patients with SCD suffering from early stages of HHAVN, core decompression has not yet been confirmed to prevent or delay natural progression of the disease. The role of arthroplasty on the other hand is promising for advanced stages. Superiority of one arthroplasty procedure over another cannot be concluded in the light of the evidence in the current review. Furthermore, its effectiveness compared with other shoulder etiologies and implant long-term survival data are not available. These researchers stated that future studies should aim to standardize data, provide longer follow-ups, and pay attention to SCD-related peri-operative complications and implant survival.
Core Decompression Combined with Intraosseous Ibandronate for Pre-Collapse Osteonecrosis of the Femoral Head
Kumar et al (2021) stated that CD is an effective method in the management of pre-collapse stage of ONFH. It has been combined with various adjuvants to increase the effectiveness including bone marrow aspirate concentration and PRP. These researchers evaluated a cheaper alternative in the form of ibandronate as an adjuvant to CD and highlighted the technique, safety, and early outcomes. Patients aged 18 to 60 years with atraumatic ONFH in the pre-collapse stage were included in the study. Subjects were followed-up to a period of 1 year and examined in terms of radiologic progression and functional outcome (MHHS and VAS). The study included 6 hips in 5patients (3 females and 2 males; age range of 18 to 57 years). There was no sign of stage progression or collapse on radiography. The average post-operative MHHS was 87.4 (73.7 to 96.7) while VAS score improved from 2.8 to 1.3 post-operatively (p = 0.00395). The authors concluded that the use of ibandronate as an adjuvant with CD showed promise. It was safe and provided good clinical improvement and was a cheaper alternative. Moreover, these researchers stated that the interpretation was limited due to the small number of patients (n = 5) and short duration of follow-up (1 year). Moreover, these researchers stated that further, large scale studies with higher number of patients and prolonged follow-up are needed to substantiate the method for recommending wider usage. Comparative trial with isolated CD is being carried out by the authors who will shed better light on additional benefit of this prospective adjuvant to CD.
References
The above policy is based on the following references:
Core Decompression of the Hip
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Core Decompression of the Other Joints
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Adjunctive Treatments
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- Yoon BH, Lee YK, Kim KC, et al. No differences in the efficacy among various core decompression modalities and non-operative treatment: A network meta-analysis. Int Orthop. 2018;42(12):2737-2743.
- Yu PA, Peng KT, Huang TW, et al. Injectable synthetic bone graft substitute combined with core decompression in the treatment of advanced osteonecrosis of the femoral head: A 5-year follow-up. Biomed J. 2015;38(3):257-261.
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- Zhang C, Fang X, Huang Z, et al. Addition of bone marrow stem cells therapy achieves better clinical outcomes and lower rates of disease progression compared with core decompression alone for early stage osteonecrosis of the femoral head: A systematic review and meta-analysis. J Am Acad Orthop Surg. 2020;28(23):973-979.
- Zhang Q, Liu L, Sun W, et al. Extracorporeal shockwave therapy in osteonecrosis of femoral head: A systematic review of now available clinical evidences. Medicine (Baltimore). 2017;96(4):e5897.
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- Zhu S, Zhang X, Chen X, et al. Comparison of cell therapy and other novel adjunctive therapies combined with core decompression for the treatment of osteonecrosis of the femoral head: A systematic review and meta-analysis of 20 studies. Bone Joint Res. 2021;10(7):445-458.
