Osteonecrosis of the femoral head (ONFH) is a refractory disease in orthopedics practice and can be divided into traumatic and non-traumatic types. Major reasons causing non-traumatic ONFH include hormone abuse, ethanol overdosage, congenital and other unknown factors. In the spring of 2003, the severe acute respiratory syndrome (SARS) broke out in most cities of China, and the patients who recovered from SARS suffered mostly from the refractory disease -ONFH. The incidence of ONFH is ∼60%-70% after SARS treatment, and ONFH mostly occurred in bilateral sides. 1 It is thought that post-SARS ONFH is mainly caused by the application of high dosage of glucocorticoid hormones during SARS treatment, though some studies indicated that other reasons might be applicable in those cases. 2,3 SARS could be one independent risk factor causing ONFH, 4, 5 perhaps via mediation by S proteins. 6 Due to unclear pathogenesis and mechanism of SARS, there has been no definitive treatment strategy for ONFH. Major treatment approaches include non-surgery (drugs, hyperbaric oxygen, extracorporeal shock wave, pulsed electromagnetic treatment, decreased loading, and proper breaking and retraction) and surgery (medullary decompression of femur, bone transplant without vessels, osteotomy, autograft bone transplantation with vessels, and artificial joint replacement). [8] [9] [10] Here, we retrospectively studied the long-term efficacies of the combined treatment (non-surgery) for 37 post-SARS patients suffering from ONFH between the end of 2003 and the end of 2015.
This is a retrospective study. A total of 44 post-SARS ONFH patients (including 74 femoral joints) were recruited between November 2013 and November 2015. Inclusive criteria: 1) matching diagnostic guideline of ONFH; 10 2) with history of SARS infection; 3) received combined treatment including alendronate, extracorporeal shock wave, and hyperbaric oxygen; and 4) obtained patient's written consents. Exclusive criteria: 1) traumatic ONFH; 2) atypical imaging manifestation or not matching diagnostic guideline; and 3) surgery treatment. This study has been approved by the ethical committee of Tianjin Hospital.
Degree of clinical pain was evaluated based on visual analog scale (VAS) approach. Harris score, as a standard evaluation to various hip disabilities and methods of treatment (full mark =100), was used for assigning good, satisfactory, acceptable and unfavorable conditions as higher than 89, 80-89, 70-79 and ,70, respectively. Imaging examination was performed on all patients. Volume and volume ratio of femoral necrosis were calculated based on magnetic resonance imaging (MRI) images. 11 All patients were examined with imaging techniques. The degree of ONFH shown on imaging was graded according to Association Research Circulation Osseous (ARCO) staging criteria. The volume and volume ratio of femoral necrosis were analyzed based on MRI images by using a published calculating method. 11 By comparing with actual measurement from surgical specimens, the MRI image-based calculation was demonstrated to be close to actual values.
All patients included in this study received the following treatment: 1) 70 mg weekly oral application of alendronate sodium for 12 consecutive years; 2) extracorporeal shock wave treatment was performed using HK.ESWL-Vm equipment (Huikang Med, Shenzhen, China). In brief, patients were fixed in a supine position with localization of the femoral necrosis region by scanning. Using 0.18-0.25 mJ/mm 2 energy density, 2-3 shocking sites were selected in single treatment for 1,000 times of shocking (60 per min). One treatment course thus consisted of 20,000-30,000 shocks. A total of 5-8 courses were performed within 2-3 months; 3) hyperbaric oxygen was performed at 1.5-fold of normal atmosphere pressure for 2 h. After 100 treatments (once daily), treatment was performed twice per week, with 5-7 days rest after every 30 treatments. In our department, each patient was re-examined monthly on VAS, Harris score and femoral joint MRI examination, which were used to calculate volume ratio of ONFH.
Measurement data were presented as mean ± SD. Paired t-test was used to compare VAS score and Harris score before and after treatment. Chi-square test was used to compare effective rate of femoral necrosis between Stage I and Stage III in the combined treatment scenario. A statistical significance was defined when p,0.05. SPSS 17.0 (SPSS Inc., Chicago, IL, USA) software was used to analyze data.
During follow-up period, 1 patient received artificial hip joint replacement, and 6 patients were lost to follow-up. Eventually, there were 37 post-SARS ONFH patients (66 hip joints) included, consisting of 6 males (11 hip joints) and 31 females (55 hip joints). All patients received prednisone treatment for 4-11 days (average =9.56±3.70 days), with a daily dosage of 180-1,430 mg (average =545.00±366.17 mg) and total dosage between 1,189 and 11,440 mg (average =4,702.22±2,826.94 mg). The average age of patients at disease onset was 29.9, ranging from 19 to 47 years. Among 37 patients, there were 29 bilateral necrosis and 8 unilateral cases. There were 14 hip joints with limb shortening by 1-2 cm. All patients presented hip joint pain to different degrees. VAS score showed 4 patients (7 hip joints) with ,5 points, 10 patients (17 joints) at 5-7 points and 23 patients (42 joints) at 8-10 points. Harris score showed 4 cases (7 joints) with good, 5 cases (8 joints) with satisfactory, 10 cases (19 joints) with acceptable and 18 cases (32 joints) with unfavorable conditions. Imaging examination of ARCO stage 12 showed 36, 21 and 9 joints at Phase I, Phase II and Phase III, respectively. 
All 37 patients (with 66 hips) were staged based on the ARCO guideline. Overall effective rate of 12-year treatment was calculated and compared among different stages. Those with enlarged necrosis volume ratio were identified as ineffective treatment, while those with unchanged or shrink volume ratio were designated as effective treatment. Among 36 hips of Stage I, effective rate was 91.67%; such figures, however, were 80.95% among 21 hips at Stage II, and only 55.56% within 9 hips at Stage III. The overall effective rate was 83.33%. Statistical analysis showed that combined therapy has different effectiveness treating femoral head necrosis at Stage I to Stage III, with the highest effective rate in Stage I patients (χ 2 =6.781, p,0.05). The improvements included the alleviation of pain and lameness and the partial recovery of hip joint functions, such as buckling and abduction. The analysis about volume ratio of femoral head bones based on MRI image indicated that enlarged volume ratio presented ineffective treatment. It can effectively delay ONFH progression after SARS treatment ( Figure 1A-F) . Among all follow-up patients, 1 of them received left artificial hip joint replacement after 5 years ( Figure 2 ); 2 patients presented digestive tract symptoms.
In our study, the average age of post-SARS ONFH patients was 29.9 years. Due to more daily activity in young people leading to heavy load on hip joints, hip joint surgery in early stages may encounter the risk of resurgery. Stringent challenge may result in patient's psychological, physiological and economic burden once undergoing surgical failure or complications. Some surgeons thus suggested conserving the femoral heads maximally instead of artificial hip joint replacement. Before making a diagnosis based on imaging evidence showing femoral head collapse, conservation treatment mainly aims to recover the function of the hip joint, to alleviate pain, and to block or retard collapse progression for curing necrosis lesion, thus improving prognosis and reducing surgical risks.
Currently, major conservation treatments include drugs, hyperbaric oxygen, extracorporeal shock, pulsed electromagnetic treatment, decreased loading, and proper breaking and retraction. [8] [9] [10] This study performed combined treatment including alendronate sodium, extracorporeal shock and hyperbaric oxygen on all included patients, followed by 12-year post-op follow-ups. Alendronate drugs can inhibit bone absorption ability of osteoclasts, accelerate osteoclast apoptosis, improve bone volume and bone strength, and facilitate bone healing, thus impeding and retarding ONFH progression, decreasing bone absorption and femoral head collapse, as well as decreasing the frequency of surgery for collapse. Hong et al showed that alendronate is one effective 13 However, due to potential side effects including jaw bone necrosis or bone fracture after long-term application of alendronate, some surgeons still prefer surgery approaches. 13 Bone et al observed 10-year study on menopausal women and found no significant correlation between alendronate drugs and bone fracture. 14 This study performed 12-year alendronate sodium treatment (70 mg weekly) on all post-SARS ONFH patients and found no jaw bone absorption or fracture among all patients. Extracorporeal shock wave therapy (ESWT) can alleviate or treat ONFH via enhancing expression of vascular endothelial growth factor (VEGF) in subchondral bones of the femoral head and induction of de novo angiogenesis to improve femoral head blood supply. Vulpiani et al found that ESWT could benefit bone reconstruction and regeneration via stimulating vascular growth factor expression. 15 , 16 Wang et al compared ESWT and surgery approach and found that ESWT had significant clinical efficacy and less probability of surgery. 17 Lin et al also showed efficacy of ESWT on prednisone treatmentinduced ONFH after systemic lupus erythematosus (SLE) treatment. 18 20 Hyperbaric oxygen environment can enhance oxygen concentration in blood, thus alleviating oxygen perfusion into bone tissues for reducing 
Prognosis of post-saRs femoral necrosis bone marrow edema, thus reducing bone pressure, venous drainage and microcirculation. Moreover, hyperbaric oxygen can also stimulate vessel angiogenesis and the function of osteoblast and osteoclast cells, thus providing necessary pre-conditions for treating ONFH. Koren et al performed an 11.1±5.1-year follow-up study and indicated that hyperbaric oxygen was 1 effective method for treating Phase I and Phase II ONFH. 21 It is still debatable about the effects of single usage of hyperbaric oxygen to treat post-SARS ONFH. Wu et al 22 performed a follow-up on Phase I ONFH of SARS patients and reported that hyperbaric oxygen cannot effectively impede or reverse progression of Phase I ONFH after SARS, while Qiu and Zhang 3 attributed hyperbaric oxygen to be a satisfactory method for treating post-SARS ONFH. This study performed regular combined treatment consisting of alendronate drug, extracorporeal shock wave and hyperbaric oxygen. By 12-year long-term follow-up, some patients showed clinical improvement of ONFH, while most patients showed retardation of disease progression or even reversion. By statistical analysis of VAS and Harris score before and after treatment, we found significant differences (p,0.05). Therefore, we believe that long-term treatment of combined therapy including alendronate drug, extracorporeal shock wave and hyperbaric oxygen could effectively retard ONFH progression, alleviate patient's clinical symptoms and improve hip joint function, thus decreasing the risk of surgery on post-SARS ONFH patients.
The current study has certain limitations. First, evaluation of treatment efficiency mainly depends on a routine body check, MRI examination and patient's interview, lacking precise pathology evidence. Second, we only compared treatment efficiency among 3 different approaches, but did not further analyze any difference between single and combined therapy.
In summary, post-SARS ONFH severely affects patients' health. Long-term combined treatment using alendronate drug, extracorporeal shock wave and hyperbaric oxygen can improve femoral head hemodynamics and osteogenesis, thus effectively managing progression of post-SARS ONFH, with significant clinical treatment efficacy, thus retarding or decreasing the risk of surgery. However, its detailed mechanism and the precise reason for post-SARS ONFH are still unclear and require further investigations.