Our study shows that ESWT can also relieve a great deal of discomfort for BMESK patients. Furthermore, the mean VAS showed a dramatic improvement from pre-treatment values at all follow-up time-points in ESWT patients, especially at t1 (1 month). The clinical improvement in WOMAC Osteoarthritis Index and SF-36 scores observed following ESWT was obvious in most patients at 1 month post-treatment (P < 0.05). These scores improved significantly earlier than those in the drug control group (P < 0.05), in which improvements were observed mainly at 3 months post-intervention. At this point, all patients had already regained a significant level of autonomy in their daily lives with a marked reduction in pain, which correlated with the progressive normalization of MRI features. Although the final outcomes of the various conservative treatments currently used are similar to those observed in some studies of ESWT, it is important to note that ESWT is a simple, non-invasive treatment that does not require the administration of pharmacological drugs, thus avoiding the reported potential side-effects . Our treatment protocol required only two therapy sessions as opposed to the time-consuming extended treatments such as pharmacological drugs.
Primary bone marrow edema syndrome is a rare, but underdiagnosed source of pain which mainly occurs around joints of the lower extremities [2, 5, 14]. There is still debate regarding the pathogenesis and implications of BME, and this is reflected in the lack of a gold standard in the treatment of this condition. Because of the reversibility of BME, conservative treatment has been recommended, including reduction of weight-bearing load, analgesic and anti-inflammatory medication and physiotherapy [5, 6, 11, 14, 15]. Reports of the use of bisphosphonates relate predominantly to their role in the treatment of BMES. Intravenous prostacyclin and bisphosphonate can be used to achieve a reduction in BME, with a considerable improvement in the accompanying symptoms . Prostacyclin improves tissue blood supply in a variety of situations through multiple mechanisms, including vasodilatation and inhibition of platelet aggregation [2, 5]. Pain relief and rapid regression of BME is attributed to the action of prostacyclin in dilating vessels and reducing capillary permeability . Bisphosphonates have been shown to improve bone density in a variety of conditions . Unfortunately, conservative treatment approaches take too long time or are unable to relieve symptoms in some cases [1, 5]. In attempting to shorten the clinical course BMES, which is invariably associated with severe and long-lasting disability, various treatments have been proposed [5, 7, 14]. Core decompression has been reported as the standard surgical treatment of recurrent or persistent painful BMES, particularly of the hip, and improves symptoms of pain through relief of intraosseous pressure [1, 2, 5, 7, 16, 17]. However, surgery is costly and associated with risks [2, 5, 6]. A consensus is required regarding the importance of an early treatment to relieve pain and to avoid weakening the bone trabeculae, which could potentially lead to a collapse or fracture of the subchondral bone . Some consider that surgery is too invasive for a self-limiting disease with a variable clinical course [2, 8, 15].
ESWT has been shown to be effective in treating many orthopedic disorders, including osteonecrosis [1, 9, 18]. Clinical trials have also highlighted the effectiveness of ESWT in treating the early stages of avascular necrosis, reducing bone edema and pain [8, 18]. There are currently few reports addressing the use of ESWT in BMES of the hip [7, 8, 11]. However, the exact mechanism by which ESWT operates remains relatively unknown. Tischer et al. demonstrated the amount of new bone formation is directly dependent on the applied EFD . Too low or too high defined energy dose for shock wave applications is disadvantageous to formation of new bone. So it is very important to select an appropriate EFD, and it can improve the efficacy of shock wave and minimize topical side effects . The close anatomical and functional links between vascular elements, marrow stromal and active bone cells may explain the positive effects of ESWT on bone metabolism . ESWT, as one of the most frequently used physical therapies, seems to be able to control inflammatory processes and to facilitate bone reparative processes as well as to activate many cellular processes critical to neovascularization and tissue regeneration [7–11]. Some animal studies have demonstrated positive results in the application of ESWT on osteonecrosis with a better induction of tissue ingrowth and neovascularization; it is associated with increased expression of angiogenic growth factors, including BMP-2, vessel endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), and proliferating cell nuclear antigen (PCNA), and it promotes cell proliferation and osteogenesis [19–21]. BMP-2 is a key mediator of bone development and repair through its capacity to mobilize osteoprogenitor cells. Increased expression of BMP-2 has been identified in femoral heads treated with ESWT, thereby promoting osteoblastic differentiation processes and resulting in bone formation . VEGF, as a specific mitogenic factor for vascular endothelial cells, may be involved in the mechanism of the positive effects of ESWT. It stimulates the proliferation of endothelial cells, promotes neovascularization, and increases vascular permeability . Finally, eNOS promotes neovascularization . It is reasonable to speculate that neovascularization plays a role in the improvement in the blood supply to the femoral head and may promote bone regeneration in cases of BMES [24, 25]. Early studies indicate that a similar effect to that of vasoactive drugs can be obtained with ESWT [9, 17]. The neo-angiogenetic effect of ESWT appears to reduce the time to symptom remission. ESWT showed significantly better clinical results and BME regression rates in MR-imaging compared to conservative treatment in combination with partial weight-bearing in the treatment of BMESK and shortens the natural course of the disease. Besides, ESWT might have the potential to avoid the need for surgical intervention according to previous studies [26, 27].
The pathophysiologic mechanism that is responsible for the dramatic pain reduction in all BMES patients following ESWT, is still unclear. ESWT for the management of BMES is easy to perform in a clinical setting and does not carry risk for the patients. Our results indicate that ESWT of BMES with increased bone turnover reduces pain by eliminating the BME and shortens the natural course of the “self-limiting disease”. The high regression rate of BME with no bone osteonecrosis present at the follow-up MRI in this study also supports the hypothesis that BMES is a distinct clinical entity, rather than an early form of bone osteonecrosis [14, 28, 29].
This study was conducted according to the CONSORT guidelines  with a rigorous study design, a clinically feasible intervention and good adherence to the programme. There are limitations associated with this study. The number of patients in the study was relatively small, and the follow-up time was relatively short, but similar to prior studies on this subject. The functional improvement in the knee was assessed subjectively using the VAS and functional scores, but no objective measures were utilized. However, the results of this study warrant confirmation in larger trials with longer follow-up periods although these studies are complicated by the off-label-use of ESWT. These patients with ESWT had not gotten any iloprost and bisphosphonate. However, we will consider combining topical ESWT with iloprost and bisphosphonate in the treatment of BMESK in future studies.