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Extracorporeal shock wave treatment can normalize painful bone marrow edema in knee osteoarthritis

Extracorporeal shock wave treatment can normalize painful bone marrow edema in knee osteoarthritis Bone marrow edema (BME) represents a reversible but highly painful finding in magnetic resonance imaging (MRI) of patients with knee osteoarthritis. The aim of this retrospective study was to evaluate the efficacy of extracorporeal shock wave treatment (ESWT) on painful BME in osteoarthritis of the knee. This study focuses on people who had early-to-mid stage osteoarthritis with knee pain and MRI findings of BME. Patients who underwent ESWT treatment or prescribed alendronate treatment in our department were analyzed. Knee pain and function were measured using the visual analog scale (VAS) for pain and the Western Ontario and McMaster University Osteoarthritis Index (WOMAC), respectively. The degree of BME was measured with MRI scans. A total of 126 patients who received ESWT treatment (Group A, n=82) or alendronate treatment (Group B, n=44) were included. All patients were followed up clinically and radiographically for a minimum of 12 months. The mean follow-up was 23.5 months (range, 12–38 months). The VAS and WOMAC score decreased more significantly after treatment in Group A than that in Group B (P<.01) within 3 months. In 6-month MRI follow-ups, there was higher incidence of distinct reduction and complete regression of BME of the affected knee in Group A than that in Group B (P<.01). ESWT is an effective, reliable, and noninvasive treatment in patients with painful BME in osteoarthritis of the knee followed by a rapid normalization of the MRI appearance. It has the potential to shorten the natural course of this disease. Abbreviations: BME = bone marrow edema, ESWT = extracorporeal shock wave treatment, VAS = visual analog scale, WOMAC = Western Ontario and McMaster University Osteoarthritis Index. Keywords: alendronate, bone marrow edema, MRI, osteoarthritis, pain, shock wave significantly increases the risk for structural progression in knee 1. Introduction osteoarthritis, and it is explained to be strongly related to Bone marrow edema (BME) represents a reversible but highly [2,5] malalignment toward the side affected by the lesion. The [1] painful finding in MR-imaging of patients with knee joint pain. increased mechanical load in knee osteoarthritic cases can cause Various diagnoses, especially such as degenerative arthritis, are microfractures to occur in the subchondral metaphyseal area, [1,2] known to contribute to BME. The exact pathogenetic [6] leading to the involved compartment collapses. Schweitzer and processes of painful BME in osteoarthritic knees and the role [4] White also stated that altered weight bearing may rightly be [3–5] are not currently known. BME in bone underneath cartilage ranked as one of the main causes of increased marrow edema lesions on MR images. BME is recognized to be related to [1,3,5,6] Editor: Helen Gharaei. biomechanical changes of knee osteoarthritis. SK, FG, JH, and TM are joint first authors. BME is usually self-limiting in the nature course and the This study was supported by the Beijing Natural Science Foundation (7174346) symptoms resolve spontaneously over a period of 6 months, or [7] and National Natural Science Foundation of China (81372013, 81672236). occasionally 12 months, which is invariably associated with [8,9] The authors have no conflicts of interest to disclose. severe and long-lasting disability. Various treatments have a b Department of Surgery, Department of Orthopedics, China-Japan Friendship been recommended in order to shorten the natural course of the Hospital, National Health and Family Planning Commission of the People’s disease. Little is known about the optimal treatment of patients Republic of China, Peking Union Medical College, Beijing, China. with this condition. The Osteoclast inhibitors such as bisphos- [9,10] Correspondence: Wei Sun, Department of Orthopedics, China–Japan phonate and parenteral prostaglandin inhibitors such as Friendship Hospital, Beijing, China (e-mail: 18901267995@163.com). [11] iloprost have been reported as being beneficial in the treatment Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc. of BME of different etiologies. Moreover, the prostaglandin This is an open access article distributed under the Creative Commons inhibitors seem to act faster and more efficacious in treatment of Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial [11] BME than other drugs, which were considered to be an ideal and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. drug for treating this disease. Sometimes, these patients undergo nonsurgical or surgical treatments, and the pain symptom is not Medicine (2018) 97:5(e9796) relieved or it may recur. Recent research supports the use of Received: 23 July 2017 / Received in final form: 10 January 2018 / Accepted: 16 January 2018 extracorporeal shock wave therapy (ESWT) in the treatment of the first stages of avascular osteonecrosis of the proximal femur http://dx.doi.org/10.1097/MD.0000000000009796 1 Kang et al. Medicine (2018) 97:5 Medicine [9,12–14] and in other conditions where BME is present. ESWT appears to be valid, reliable, and noninvasive to rapidly resolve intractable BME syndrome of the hip, and it has a low complication rate and relatively low cost compared with other [15] conservative and surgical treatment approaches. It has been shown to activate many cellular processes critical to neo- [16,17] vascularization and tissue regeneration. However, there have been no reports on the clinical results of BME in osteoarthritis of the knee treated with ESWT. In this study, we retrospectively evaluated the efficacy of ESWT on painful BME in osteoarthritis of the knee, to explore whether shock wave treatment can shorten the natural course of this disease. We hypothesized that topical ESWT would result in rapid pain relief and functional improvement of the affected knee with BME without substantial complications. 2. Methods The comparative historical cohort study was approved by the Institutional Review Board on Human Studies of the Ethical Committee of China–Japan Friendship Hospital, and the study procedures adhered to the 1975 Declaration of Helsinki. Informed consent was obtained from all the patients. The study comprised early-to-mid stage osteoarthritic patients who had presented between January 2012 and July 2015 with knee pain and who had magnetic resonance imaging (MRI) findings of BME. All the patients included in this study had early- to-mid stage osteoarthritis with knee pain, no history or recall of trauma, and no valgus or varus deformity. Patients who had received any previous treatment or other diagnoses were also excluded, along with those who had contraindications for [12] ESWT. The study included 126 osteoarthritic patients who had presented with knee pain and whose MRIs showed BME at Figure 2. Intratherapeutic extracorporeal shock wave photograph of patients our center (Fig. 1). There were 71 females and 55 males, and their involved in the study. mean age was 51.9 years (range, 39–73 years) in this study. An evaluation of body mass index (BMI) showed as 26.8±4.1kg/m . Patients who underwent ESWT treatment (Fig. 2) (Group A, n= onset of symptoms and the beginning of treatment was 5.6 weeks 82) or prescribed alendronate treatment (Group B, n=44) in our department were analyzed (70mg po qw; Merck & Co, Inc, (range 1–12 weeks). The pain was in the right knee in 79 patients Peking) (Table 1). They complained of continuous pain while and in the left knee in 47 patients. The mean follow-up period walking, which eased with rest. The average time between the was 23.5 months (range, 12–38 months). Figure 1. The MRI T2-weighted images (C) showing a large bone marrow edema within the medial femoral condyle (white arrow) and medial tibial plateau (white arrowhead) of the left osteoarthritic knee (K-L Grade 2), (A) posteroanterior view and (B) lateral view of x-ray, in a 64-year-old male patient. MRI = magnetic resonance imaging. 2 Kang et al. Medicine (2018) 97:5 www.md-journal.com qd for 2 weeks; Beijing Tide Pharmaceutical Co, Ltd; Beijing). Table 1 The postintervention results were evaluated by the visual analog Patients characteristics. scale (VAS), WOMAC, and MRI scans as well as plain Characteristics Group A (n= 82) Group B (n= 44) radiographs at 2 weeks (without imaging examination), 1 Female, n (%) 47 (57.3) 24 (54.5) months (without imaging examination), 3 months, 6 months, Age, years 50.9± 9.2 52.6± 8.7 1 year post-treatment, and after. Routine evaluation of the BMI, kg/m 27.6± 4.7 25.3± 5.2 mechanical axis was made by full-weight-bearing anterior– IBST, weeks 6.1± 5.1 5.2± 3.8 posterior-lateral knee radiographs and leg length radiographs. Kellgren–Lawrence criteria Grade 1 21 10 Grade 2 52 29 2.3. Statistical analysis Grade 3 9 5 All data analyses were performed using SPSS version 16.0.0 Haavardsholm MRI grade software (SPSS; Chicago, IL). The means and standard deviations Grade 1 11 7 (SD) were calculated for all patients, and 95% confidence Grade 2 24 17 Grade 3 47 20 intervals (CIs) were determined. The paired t test (Gaussian FU time, months 23.1± 11.5 24.7± 9.2 population) or Wilcoxon test (non-Gaussian population) was used to determine the changes in the VAS and WOMAC knee All P> .05. scores. A probability (P) value<.05 was considered to be of BMI = body mass index; FU = follow up, IBST = interval between the onset of symptoms and the beginning of treatment, MRI = magnetic resonance imaging. statistical significance. The degree of osteoarthritis was categorized radiologically 3. Results [18] according to the Kellgren–Lawrence (K-L) grading system (Fig. 1A and B). According to the K-L criteria, 31 cases were 3.1. Clinical outcome Grade 1, 81 cases were Grade 2, and 14 cases were Grade 3. An The compared results of the development of the VAS for pain and experienced radiologist evaluated the extent of edema on 1 slide the Western Ontario and McMaster University Osteoarthritis with the most obvious edema of the resulting MRI films with the Index (WOMAC) between both groups are shown in Figures 3 same fluid-sensitive sequence using the PACS software (Kodak and 4. In this study, the overall VAS and WOMAC score version 11.0, MA) to verify whether the edema lesion showed decreased significantly in both groups at the final follow-up time unchanged, reduced, or regressed completely. The BME was (P<.01). All patients described the daily life function as categorized according to the width of the lesions extending into significantly improved. This might be mainly caused by pain the joint surface subchondral area on MRI T2 sequences as relief. Compared with Group B, all patients in Group A showed a follows: Grade 0, no edema; Grade 1, minimal (<5mm greater and earlier improvement in VAS pain score and WOMAC diameter); Grade 2, mild (5–20mm diameter); Grade 3, severe score at the last follow-up after therapeutic intervention (P<.01). [19] (>20mm diameter) (Fig. 1C). The degree of BME on MRI was Moreover, VAS pain score of all patients in Group A continued to evaluated as follows: 18 cases of Grade 1, 41 cases of Grade 2, improve more obviously over the follow-up period than that in and 67 cases of Grade 3. Group B (Fig. 3). Significant improvement in the VAS score was observed in Group A, from 8.5±1.3 to 3.4±2.1 points at 2 2.1. Shock wave treatment weeks, to 2.0±1.4 points at 1 month, to 1.1±0.9 points at 3 months, to 0.9±0.6 points at 6 months, and to 0.5±0.5 points at The shock wave treatment was applied under intensified surface 12 months after therapeutic intervention. Gradual improvement anesthesia (lidocaine hydrochloride gel) combined with once- in the VAS was shown in Group B, from 8.2±1.5 points to 5.8± through intravenous flurbiprofen axetil (Beijing Tide Pharma- 1.9 points at 2 weeks, to 4.6±1.8 points at 1 month, to 3.1±2.0 ceutical Co, Ltd, Beijing) using an Electromagnetic Shock Wave points at 3 months, to 2.2±1.1 points at 6 months, and to 1.4± Emitter (Dornier Compact DELTA II, Germany) (Fig. 2), with a penetration depth of between 0 and 150mm and a focus diameter of 4mm. Shock waves were focused around (on the margins of) the knee under radiographic guidance. The treatment area was prepared with a coupling gel to minimize the loss of shock wave energy at the interface between the head of the device and the [13,15,29] skin. The patients were subjected to high-energy ESWT, and the parameters are prepared and used as follows: number of levels, 3–4; at a high energy flux density of >0.44mJ/mm (level 3); 3000 to 4000 impulses at a frequency of 2 to 3Hz. Each patient underwent 2 therapy sessions (the time interval between successive procedures was 1 week). The number of the frequency selected depends on the patient’s condition. 2.2. Postintervention management and follow-up All patients were mobilized with partial weight bearing and Figure 3. The development of the VAS during therapeutical intervention on walking aids for 6 weeks and analgesics on demand with BME in the knee osteoarthritis between 2 groups. BME = bone marrow edema, restrictions for impact sports such as sprinting or jumping. VAS = visual analog scale. Patients in both groups received intravenous alprostadil (10mg, 3 Kang et al. Medicine (2018) 97:5 Medicine detected with alendronate. Over the study period, no case of osteonecrosis of the jaw or a kidney dysfunction was noted in the alendronate oral medication. No other adverse effects were noted. But there was a special case of intra-articular shifting painful BME of knee osteoarthritis with treated ESWT plus alprostadil. We described the case hereinbelow. 3.4. One case with intra-articular shifting BME There was 1 case with intra-articular shifting BME, hence which was excluded in this study. Painful BME in the left knee osteoarthritis was diagnosed in a 50-year-old male driver. ESWT rapidly produced positive effects with regard to both pain and BME. Symptoms of pain were significantly relieved. The painful VAS score dropped from 9 points preoperatively to 2 points at 2 Figure 4. The development of the WOMAC score during therapeutical weeks post-treatment, and disappeared at 1 month post- intervention on BME in the knee osteoarthritis between 2 groups. BME = bone treatment. However, the sudden intense pain occurs in his left marrow edema, WOMAC = Western Ontario and McMaster University knee at 9 weeks post-treatment. MRI showed BME recurred and Osteoarthritis Index. was involved in lateral condyle of femur. He received the same treatment option. Patients treated with ESWT recover quickly and experience a rapid relief from pain. Accompanied by improvements in the WOMAC Osteoarthritis Index and VAS, 0.9 points at 12 months after therapeutic intervention. The mean MRI showed a significant regression in edema between the improvement of WOMAC score after therapeutic intervention pretreatment and 3 months post second treatment. At the between both groups during the follow-up time was statistically 12-month follow-up MRI BME was not seen to have recurred in significant (P<.01) (Fig. 4). Significant improvement in the the patient. WOMAC score was observed in Group A, from 67.1±9.7 to 27.9±10.1 points at 2 weeks, to 19.5±11 points at 1 month, to 9.8±9.8 points at 3 months, to 8.6±9.5 points at 6 months, and 4. Discussion to 7.4±5.8 points at 12 months after therapeutic intervention. Several reasons are known for pain in osteoarthritic knees. All Gradual improvement in the WOMAC was shown in Group B, patients with BME can also suffer severe pain. Several studies from 65.9±10.4 to 48.2±11.2 points at 2 weeks, to 41.1±9.8 have stated a relationship between BME and pain and that a points at 1 month, to 26.3±10.2 points at 3 months, to 21.9±9.1 [2,5,15,20] decrease in BME lesions reduces the pain. In our study, points at 6 months, and to 19.4±8.3 points at 12 months after the regression in the BME and the reduction in pain following therapeutic intervention. ESWT plus alprostadil can also support the idea of a relationship between BME and pain. However, the exact frequency of BME in 3.2. Radiological outcome patients with osteoarthritis of the knee is not known. The presence of BME was noted on MRI in 50% to 73% of painful The MRI findings demonstrated the progressive regression of the [5,21] knees and also in a few of pain-free knees. BME is strongly BME in both groups. MRI scans of both groups showed that the related to malalignment toward the affected side, which increases patients in Group A had a higher incidence of distinct reduction [2,5] the risk for structural progression in knee osteoarthritis. The and complete regression of BME at 3 months (90.2% vs 61.4%; altered weight bearing may be 1 reason why marrow edema P<.001). The MRI at 6-month follow-up in Group A showed lesions on MR images increased in the subchondral metaphyseal that there were a distinct reduction of BME in 61 patients and [4] area. And biomechanical changes of knee osteoarthritis can complete regression in 17 patients, so total improvement rate was cause microfractures to occur, leading to BME in the involved 95.1% (78/82). In Group B, there was a reduction in BME in 21 [6,22] compartment. Besides, high BMI and knee deformities are patients and complete regression in 14 patients, moreover, total the high-risk factors affecting the occurrence of BME lesions on improvement rate was 79.5% (35/44). There was an apparent [2] MRI in knee osteoarthritis, which, in turn, would show a significant difference between 2 groups in the MRI improvement tendency to speed up the progression of osteoarthritis. rate (P=.006). However, the MRI at 12-month follow-up Histologically, it showed that abnormal bone trabeculae, small showed that there were complete regression in all patients in areas of osteonecrosis, and wide areas of remodeling can be Group A (100%) and most of patients in Group B (97.7%). [23] observed in the area of BME. The venous stasis and increased However, 1 case in Group B continued to normalize over the bone pressure may occur in the bone marrow lesions near the subsequent follow-up period (18 months). Therefore, these MRI painful joint where abnormally high uptake of the radiotracer results at the final follow-up were not statistically significant. In [24] appears. However, there is still debate regarding the the final follow-up, there was no joint space narrowing found, no pathogenesis and implications of BME in knee osteoarthritis. necrosis, or stress fracture of the knee seen in this study. There is no consensus regarding treatment for BME seen on [2,3,5,8,25] MRI in osteoarthritic knees. Conservative treatment is 3.3. Side-effects recommended to be able to regress BME, including reduction of Only minor complications occurred after ESWT, such as weight-bearing load, analgesic and anti-inflammatory medica- [3,8,26,27] transient soft tissue swelling or minor bruising. No clinically tion, and physiotherapy. The potent osteoclast inhibitor detectable neuromuscular, systemic, or device-related adverse alendronate has proved to be effective and tolerant in metabolic [10,28,29] effects were observed after ESWT. No adverse events were bone disease such as osteoporosis conditions and BME. 4 Kang et al. Medicine (2018) 97:5 www.md-journal.com However, the pathophysiological mechanism of action of was assessed subjectively using the VAS and functional scores, alendronate in BME is still unclear. It seems that bisphosphonate but no objective measures were utilized. The follow-up time treatment can regulate the increased bone turnover in BME to was relatively short, but similar to prior studies on this subject. [10] shorten the natural course of the disease. However, This study was only a pilot clinical study. However, the results conservative treatment approaches take too long time or are of this study were inspiring. Moreover, we will consider [1,8] unable to relieve symptoms in some cases. Surgeries such as multicenter randomized controlled trials to validate this core decompression or open-wedge tibial osteotomy, which can conclusion in future studies. shorten the clinical course, are costly and associated with [2,8,26,30] risks. Moreover, some considered that surgery was too 5. Conclusion invasive for a self-limiting disease with a variable clinical [12,30] In conclusion, extracorporeal shock wave treatment was an course. Clinical trials have confirmed the effectiveness of effective, reliable, and noninvasive treatment in patients who ESWT in treating the early stages of avascular necrosis, reducing [13,31] have painful BME in osteoarthritis of the knee, followed by a bone edema, and pain. There have been currently a few rapid normalization of the MRI appearance. They seemed to act reports addressing the use of ESWT in idiopathic BME of the [9,12,15] faster and more efficacious with a lower complication rate. It has hip. Our study showed that ESWT would result in more the potential to resolve patient suffering quickly. It was explored highly effective pain relief and functional improvement of the to shorten the natural course of this disease. To ensure our results, affected knee without substantial complications in painful BME prospective randomized trials with long-terms results should be in knee osteoarthritic patients than alendronate oral medication. realized. Further exploration of its mechanisms and prospects And the mean VAS showed a more dramatic improvement from would be worthwhile. pretreatment values at all follow-up time, especially at 1 month. The clinical improvement in WOMAC Osteoarthritis Index observed following ESWT was more obvious in most patients at 1 References month post-treatment than the control Group (P<.01). At the [1] Berger CE, Kröner AH, Kristen KH, et al. Transient bone marrow final follow-up point, all patients had already regained a edema syndrome of the knee: clinical and magnetic resonance imaging significant level of autonomy in their daily lives with a marked results at 5 years after core decompression. Arthroscopy 2006;22: reduction in pain, which correlated with the progressive 866–71. normalization of MRI features. It showed that ESWT method [2] Kesemenli CC, Memisoglu K, Muezzinoglu US, et al. Treatment for painful bone marrow edema by open wedge tibial osteotomy. 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Extracorporeal shock wave treatment can normalize painful bone marrow edema in knee osteoarthritis

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Wolters Kluwer Health
Copyright
Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.
ISSN
0025-7974
eISSN
1536-5964
DOI
10.1097/MD.0000000000009796
pmid
29384878
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Abstract

Bone marrow edema (BME) represents a reversible but highly painful finding in magnetic resonance imaging (MRI) of patients with knee osteoarthritis. The aim of this retrospective study was to evaluate the efficacy of extracorporeal shock wave treatment (ESWT) on painful BME in osteoarthritis of the knee. This study focuses on people who had early-to-mid stage osteoarthritis with knee pain and MRI findings of BME. Patients who underwent ESWT treatment or prescribed alendronate treatment in our department were analyzed. Knee pain and function were measured using the visual analog scale (VAS) for pain and the Western Ontario and McMaster University Osteoarthritis Index (WOMAC), respectively. The degree of BME was measured with MRI scans. A total of 126 patients who received ESWT treatment (Group A, n=82) or alendronate treatment (Group B, n=44) were included. All patients were followed up clinically and radiographically for a minimum of 12 months. The mean follow-up was 23.5 months (range, 12–38 months). The VAS and WOMAC score decreased more significantly after treatment in Group A than that in Group B (P<.01) within 3 months. In 6-month MRI follow-ups, there was higher incidence of distinct reduction and complete regression of BME of the affected knee in Group A than that in Group B (P<.01). ESWT is an effective, reliable, and noninvasive treatment in patients with painful BME in osteoarthritis of the knee followed by a rapid normalization of the MRI appearance. It has the potential to shorten the natural course of this disease. Abbreviations: BME = bone marrow edema, ESWT = extracorporeal shock wave treatment, VAS = visual analog scale, WOMAC = Western Ontario and McMaster University Osteoarthritis Index. Keywords: alendronate, bone marrow edema, MRI, osteoarthritis, pain, shock wave significantly increases the risk for structural progression in knee 1. Introduction osteoarthritis, and it is explained to be strongly related to Bone marrow edema (BME) represents a reversible but highly [2,5] malalignment toward the side affected by the lesion. The [1] painful finding in MR-imaging of patients with knee joint pain. increased mechanical load in knee osteoarthritic cases can cause Various diagnoses, especially such as degenerative arthritis, are microfractures to occur in the subchondral metaphyseal area, [1,2] known to contribute to BME. The exact pathogenetic [6] leading to the involved compartment collapses. Schweitzer and processes of painful BME in osteoarthritic knees and the role [4] White also stated that altered weight bearing may rightly be [3–5] are not currently known. BME in bone underneath cartilage ranked as one of the main causes of increased marrow edema lesions on MR images. BME is recognized to be related to [1,3,5,6] Editor: Helen Gharaei. biomechanical changes of knee osteoarthritis. SK, FG, JH, and TM are joint first authors. BME is usually self-limiting in the nature course and the This study was supported by the Beijing Natural Science Foundation (7174346) symptoms resolve spontaneously over a period of 6 months, or [7] and National Natural Science Foundation of China (81372013, 81672236). occasionally 12 months, which is invariably associated with [8,9] The authors have no conflicts of interest to disclose. severe and long-lasting disability. Various treatments have a b Department of Surgery, Department of Orthopedics, China-Japan Friendship been recommended in order to shorten the natural course of the Hospital, National Health and Family Planning Commission of the People’s disease. Little is known about the optimal treatment of patients Republic of China, Peking Union Medical College, Beijing, China. with this condition. The Osteoclast inhibitors such as bisphos- [9,10] Correspondence: Wei Sun, Department of Orthopedics, China–Japan phonate and parenteral prostaglandin inhibitors such as Friendship Hospital, Beijing, China (e-mail: 18901267995@163.com). [11] iloprost have been reported as being beneficial in the treatment Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc. of BME of different etiologies. Moreover, the prostaglandin This is an open access article distributed under the Creative Commons inhibitors seem to act faster and more efficacious in treatment of Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial [11] BME than other drugs, which were considered to be an ideal and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. drug for treating this disease. Sometimes, these patients undergo nonsurgical or surgical treatments, and the pain symptom is not Medicine (2018) 97:5(e9796) relieved or it may recur. Recent research supports the use of Received: 23 July 2017 / Received in final form: 10 January 2018 / Accepted: 16 January 2018 extracorporeal shock wave therapy (ESWT) in the treatment of the first stages of avascular osteonecrosis of the proximal femur http://dx.doi.org/10.1097/MD.0000000000009796 1 Kang et al. Medicine (2018) 97:5 Medicine [9,12–14] and in other conditions where BME is present. ESWT appears to be valid, reliable, and noninvasive to rapidly resolve intractable BME syndrome of the hip, and it has a low complication rate and relatively low cost compared with other [15] conservative and surgical treatment approaches. It has been shown to activate many cellular processes critical to neo- [16,17] vascularization and tissue regeneration. However, there have been no reports on the clinical results of BME in osteoarthritis of the knee treated with ESWT. In this study, we retrospectively evaluated the efficacy of ESWT on painful BME in osteoarthritis of the knee, to explore whether shock wave treatment can shorten the natural course of this disease. We hypothesized that topical ESWT would result in rapid pain relief and functional improvement of the affected knee with BME without substantial complications. 2. Methods The comparative historical cohort study was approved by the Institutional Review Board on Human Studies of the Ethical Committee of China–Japan Friendship Hospital, and the study procedures adhered to the 1975 Declaration of Helsinki. Informed consent was obtained from all the patients. The study comprised early-to-mid stage osteoarthritic patients who had presented between January 2012 and July 2015 with knee pain and who had magnetic resonance imaging (MRI) findings of BME. All the patients included in this study had early- to-mid stage osteoarthritis with knee pain, no history or recall of trauma, and no valgus or varus deformity. Patients who had received any previous treatment or other diagnoses were also excluded, along with those who had contraindications for [12] ESWT. The study included 126 osteoarthritic patients who had presented with knee pain and whose MRIs showed BME at Figure 2. Intratherapeutic extracorporeal shock wave photograph of patients our center (Fig. 1). There were 71 females and 55 males, and their involved in the study. mean age was 51.9 years (range, 39–73 years) in this study. An evaluation of body mass index (BMI) showed as 26.8±4.1kg/m . Patients who underwent ESWT treatment (Fig. 2) (Group A, n= onset of symptoms and the beginning of treatment was 5.6 weeks 82) or prescribed alendronate treatment (Group B, n=44) in our department were analyzed (70mg po qw; Merck & Co, Inc, (range 1–12 weeks). The pain was in the right knee in 79 patients Peking) (Table 1). They complained of continuous pain while and in the left knee in 47 patients. The mean follow-up period walking, which eased with rest. The average time between the was 23.5 months (range, 12–38 months). Figure 1. The MRI T2-weighted images (C) showing a large bone marrow edema within the medial femoral condyle (white arrow) and medial tibial plateau (white arrowhead) of the left osteoarthritic knee (K-L Grade 2), (A) posteroanterior view and (B) lateral view of x-ray, in a 64-year-old male patient. MRI = magnetic resonance imaging. 2 Kang et al. Medicine (2018) 97:5 www.md-journal.com qd for 2 weeks; Beijing Tide Pharmaceutical Co, Ltd; Beijing). Table 1 The postintervention results were evaluated by the visual analog Patients characteristics. scale (VAS), WOMAC, and MRI scans as well as plain Characteristics Group A (n= 82) Group B (n= 44) radiographs at 2 weeks (without imaging examination), 1 Female, n (%) 47 (57.3) 24 (54.5) months (without imaging examination), 3 months, 6 months, Age, years 50.9± 9.2 52.6± 8.7 1 year post-treatment, and after. Routine evaluation of the BMI, kg/m 27.6± 4.7 25.3± 5.2 mechanical axis was made by full-weight-bearing anterior– IBST, weeks 6.1± 5.1 5.2± 3.8 posterior-lateral knee radiographs and leg length radiographs. Kellgren–Lawrence criteria Grade 1 21 10 Grade 2 52 29 2.3. Statistical analysis Grade 3 9 5 All data analyses were performed using SPSS version 16.0.0 Haavardsholm MRI grade software (SPSS; Chicago, IL). The means and standard deviations Grade 1 11 7 (SD) were calculated for all patients, and 95% confidence Grade 2 24 17 Grade 3 47 20 intervals (CIs) were determined. The paired t test (Gaussian FU time, months 23.1± 11.5 24.7± 9.2 population) or Wilcoxon test (non-Gaussian population) was used to determine the changes in the VAS and WOMAC knee All P> .05. scores. A probability (P) value<.05 was considered to be of BMI = body mass index; FU = follow up, IBST = interval between the onset of symptoms and the beginning of treatment, MRI = magnetic resonance imaging. statistical significance. The degree of osteoarthritis was categorized radiologically 3. Results [18] according to the Kellgren–Lawrence (K-L) grading system (Fig. 1A and B). According to the K-L criteria, 31 cases were 3.1. Clinical outcome Grade 1, 81 cases were Grade 2, and 14 cases were Grade 3. An The compared results of the development of the VAS for pain and experienced radiologist evaluated the extent of edema on 1 slide the Western Ontario and McMaster University Osteoarthritis with the most obvious edema of the resulting MRI films with the Index (WOMAC) between both groups are shown in Figures 3 same fluid-sensitive sequence using the PACS software (Kodak and 4. In this study, the overall VAS and WOMAC score version 11.0, MA) to verify whether the edema lesion showed decreased significantly in both groups at the final follow-up time unchanged, reduced, or regressed completely. The BME was (P<.01). All patients described the daily life function as categorized according to the width of the lesions extending into significantly improved. This might be mainly caused by pain the joint surface subchondral area on MRI T2 sequences as relief. Compared with Group B, all patients in Group A showed a follows: Grade 0, no edema; Grade 1, minimal (<5mm greater and earlier improvement in VAS pain score and WOMAC diameter); Grade 2, mild (5–20mm diameter); Grade 3, severe score at the last follow-up after therapeutic intervention (P<.01). [19] (>20mm diameter) (Fig. 1C). The degree of BME on MRI was Moreover, VAS pain score of all patients in Group A continued to evaluated as follows: 18 cases of Grade 1, 41 cases of Grade 2, improve more obviously over the follow-up period than that in and 67 cases of Grade 3. Group B (Fig. 3). Significant improvement in the VAS score was observed in Group A, from 8.5±1.3 to 3.4±2.1 points at 2 2.1. Shock wave treatment weeks, to 2.0±1.4 points at 1 month, to 1.1±0.9 points at 3 months, to 0.9±0.6 points at 6 months, and to 0.5±0.5 points at The shock wave treatment was applied under intensified surface 12 months after therapeutic intervention. Gradual improvement anesthesia (lidocaine hydrochloride gel) combined with once- in the VAS was shown in Group B, from 8.2±1.5 points to 5.8± through intravenous flurbiprofen axetil (Beijing Tide Pharma- 1.9 points at 2 weeks, to 4.6±1.8 points at 1 month, to 3.1±2.0 ceutical Co, Ltd, Beijing) using an Electromagnetic Shock Wave points at 3 months, to 2.2±1.1 points at 6 months, and to 1.4± Emitter (Dornier Compact DELTA II, Germany) (Fig. 2), with a penetration depth of between 0 and 150mm and a focus diameter of 4mm. Shock waves were focused around (on the margins of) the knee under radiographic guidance. The treatment area was prepared with a coupling gel to minimize the loss of shock wave energy at the interface between the head of the device and the [13,15,29] skin. The patients were subjected to high-energy ESWT, and the parameters are prepared and used as follows: number of levels, 3–4; at a high energy flux density of >0.44mJ/mm (level 3); 3000 to 4000 impulses at a frequency of 2 to 3Hz. Each patient underwent 2 therapy sessions (the time interval between successive procedures was 1 week). The number of the frequency selected depends on the patient’s condition. 2.2. Postintervention management and follow-up All patients were mobilized with partial weight bearing and Figure 3. The development of the VAS during therapeutical intervention on walking aids for 6 weeks and analgesics on demand with BME in the knee osteoarthritis between 2 groups. BME = bone marrow edema, restrictions for impact sports such as sprinting or jumping. VAS = visual analog scale. Patients in both groups received intravenous alprostadil (10mg, 3 Kang et al. Medicine (2018) 97:5 Medicine detected with alendronate. Over the study period, no case of osteonecrosis of the jaw or a kidney dysfunction was noted in the alendronate oral medication. No other adverse effects were noted. But there was a special case of intra-articular shifting painful BME of knee osteoarthritis with treated ESWT plus alprostadil. We described the case hereinbelow. 3.4. One case with intra-articular shifting BME There was 1 case with intra-articular shifting BME, hence which was excluded in this study. Painful BME in the left knee osteoarthritis was diagnosed in a 50-year-old male driver. ESWT rapidly produced positive effects with regard to both pain and BME. Symptoms of pain were significantly relieved. The painful VAS score dropped from 9 points preoperatively to 2 points at 2 Figure 4. The development of the WOMAC score during therapeutical weeks post-treatment, and disappeared at 1 month post- intervention on BME in the knee osteoarthritis between 2 groups. BME = bone treatment. However, the sudden intense pain occurs in his left marrow edema, WOMAC = Western Ontario and McMaster University knee at 9 weeks post-treatment. MRI showed BME recurred and Osteoarthritis Index. was involved in lateral condyle of femur. He received the same treatment option. Patients treated with ESWT recover quickly and experience a rapid relief from pain. Accompanied by improvements in the WOMAC Osteoarthritis Index and VAS, 0.9 points at 12 months after therapeutic intervention. The mean MRI showed a significant regression in edema between the improvement of WOMAC score after therapeutic intervention pretreatment and 3 months post second treatment. At the between both groups during the follow-up time was statistically 12-month follow-up MRI BME was not seen to have recurred in significant (P<.01) (Fig. 4). Significant improvement in the the patient. WOMAC score was observed in Group A, from 67.1±9.7 to 27.9±10.1 points at 2 weeks, to 19.5±11 points at 1 month, to 9.8±9.8 points at 3 months, to 8.6±9.5 points at 6 months, and 4. Discussion to 7.4±5.8 points at 12 months after therapeutic intervention. Several reasons are known for pain in osteoarthritic knees. All Gradual improvement in the WOMAC was shown in Group B, patients with BME can also suffer severe pain. Several studies from 65.9±10.4 to 48.2±11.2 points at 2 weeks, to 41.1±9.8 have stated a relationship between BME and pain and that a points at 1 month, to 26.3±10.2 points at 3 months, to 21.9±9.1 [2,5,15,20] decrease in BME lesions reduces the pain. In our study, points at 6 months, and to 19.4±8.3 points at 12 months after the regression in the BME and the reduction in pain following therapeutic intervention. ESWT plus alprostadil can also support the idea of a relationship between BME and pain. However, the exact frequency of BME in 3.2. Radiological outcome patients with osteoarthritis of the knee is not known. The presence of BME was noted on MRI in 50% to 73% of painful The MRI findings demonstrated the progressive regression of the [5,21] knees and also in a few of pain-free knees. BME is strongly BME in both groups. MRI scans of both groups showed that the related to malalignment toward the affected side, which increases patients in Group A had a higher incidence of distinct reduction [2,5] the risk for structural progression in knee osteoarthritis. The and complete regression of BME at 3 months (90.2% vs 61.4%; altered weight bearing may be 1 reason why marrow edema P<.001). The MRI at 6-month follow-up in Group A showed lesions on MR images increased in the subchondral metaphyseal that there were a distinct reduction of BME in 61 patients and [4] area. And biomechanical changes of knee osteoarthritis can complete regression in 17 patients, so total improvement rate was cause microfractures to occur, leading to BME in the involved 95.1% (78/82). In Group B, there was a reduction in BME in 21 [6,22] compartment. Besides, high BMI and knee deformities are patients and complete regression in 14 patients, moreover, total the high-risk factors affecting the occurrence of BME lesions on improvement rate was 79.5% (35/44). There was an apparent [2] MRI in knee osteoarthritis, which, in turn, would show a significant difference between 2 groups in the MRI improvement tendency to speed up the progression of osteoarthritis. rate (P=.006). However, the MRI at 12-month follow-up Histologically, it showed that abnormal bone trabeculae, small showed that there were complete regression in all patients in areas of osteonecrosis, and wide areas of remodeling can be Group A (100%) and most of patients in Group B (97.7%). [23] observed in the area of BME. The venous stasis and increased However, 1 case in Group B continued to normalize over the bone pressure may occur in the bone marrow lesions near the subsequent follow-up period (18 months). Therefore, these MRI painful joint where abnormally high uptake of the radiotracer results at the final follow-up were not statistically significant. In [24] appears. However, there is still debate regarding the the final follow-up, there was no joint space narrowing found, no pathogenesis and implications of BME in knee osteoarthritis. necrosis, or stress fracture of the knee seen in this study. There is no consensus regarding treatment for BME seen on [2,3,5,8,25] MRI in osteoarthritic knees. Conservative treatment is 3.3. Side-effects recommended to be able to regress BME, including reduction of Only minor complications occurred after ESWT, such as weight-bearing load, analgesic and anti-inflammatory medica- [3,8,26,27] transient soft tissue swelling or minor bruising. No clinically tion, and physiotherapy. The potent osteoclast inhibitor detectable neuromuscular, systemic, or device-related adverse alendronate has proved to be effective and tolerant in metabolic [10,28,29] effects were observed after ESWT. No adverse events were bone disease such as osteoporosis conditions and BME. 4 Kang et al. Medicine (2018) 97:5 www.md-journal.com However, the pathophysiological mechanism of action of was assessed subjectively using the VAS and functional scores, alendronate in BME is still unclear. It seems that bisphosphonate but no objective measures were utilized. The follow-up time treatment can regulate the increased bone turnover in BME to was relatively short, but similar to prior studies on this subject. [10] shorten the natural course of the disease. However, This study was only a pilot clinical study. However, the results conservative treatment approaches take too long time or are of this study were inspiring. Moreover, we will consider [1,8] unable to relieve symptoms in some cases. Surgeries such as multicenter randomized controlled trials to validate this core decompression or open-wedge tibial osteotomy, which can conclusion in future studies. shorten the clinical course, are costly and associated with [2,8,26,30] risks. Moreover, some considered that surgery was too 5. Conclusion invasive for a self-limiting disease with a variable clinical [12,30] In conclusion, extracorporeal shock wave treatment was an course. Clinical trials have confirmed the effectiveness of effective, reliable, and noninvasive treatment in patients who ESWT in treating the early stages of avascular necrosis, reducing [13,31] have painful BME in osteoarthritis of the knee, followed by a bone edema, and pain. There have been currently a few rapid normalization of the MRI appearance. They seemed to act reports addressing the use of ESWT in idiopathic BME of the [9,12,15] faster and more efficacious with a lower complication rate. It has hip. Our study showed that ESWT would result in more the potential to resolve patient suffering quickly. It was explored highly effective pain relief and functional improvement of the to shorten the natural course of this disease. To ensure our results, affected knee without substantial complications in painful BME prospective randomized trials with long-terms results should be in knee osteoarthritic patients than alendronate oral medication. realized. Further exploration of its mechanisms and prospects And the mean VAS showed a more dramatic improvement from would be worthwhile. pretreatment values at all follow-up time, especially at 1 month. The clinical improvement in WOMAC Osteoarthritis Index observed following ESWT was more obvious in most patients at 1 References month post-treatment than the control Group (P<.01). At the [1] Berger CE, Kröner AH, Kristen KH, et al. Transient bone marrow final follow-up point, all patients had already regained a edema syndrome of the knee: clinical and magnetic resonance imaging significant level of autonomy in their daily lives with a marked results at 5 years after core decompression. Arthroscopy 2006;22: reduction in pain, which correlated with the progressive 866–71. normalization of MRI features. It showed that ESWT method [2] Kesemenli CC, Memisoglu K, Muezzinoglu US, et al. Treatment for painful bone marrow edema by open wedge tibial osteotomy. 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MedicineWolters Kluwer Health

Published: Feb 1, 2018

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