The Clinical Effect On The Osseous Structure And Collapse Risk After Huo-Gu Formula Treatment For Osteonecrosis Of Femoral Head

BackgroundHuo-Gu Formula(HGF),a Traditional Chinese Medicine(TCM)prescription,is created according to the unique theory "Conditioning the spleen to treat osteonecrosis of femoral head(ONFH)".HGF is derived from the classic theories of TCM orthopedics and traumatology.It has been used in clinical practice for a long term,and its medicinal material basis and mechanism of action have been repeatedly tested.Early short-term clinical studies have found the effect of HGF on improving physical function and reducing the rate of femoral head collapse,but its long-term effect still needs long-term follow-up evaluation.Bone repair is an important process that directly affects the long-term clinical outcome of ONFH.Previous studies have shown that HGF has the effect of reducing the rate of empty bone lacuna and promoting bone formation,so as to promote the bone repair process.However,the clinical process of HGF to promote bone repair needs further exploration.In fact,the process of bone repair lacks analytical methods for objective measurement and continuous comparison in clinical practice.The CT image of the femoral head stores a large amount of biological information:the osseous component information and the components with soft tissue properties that have not been studied in earlier studies,including bone marrow and other tissue components that accompany the bone repair process.This information,based on the concept to establish medical imaging bio-markers,might help create the analysis method to reveal the clinical process of HGF to promote bone repair.Objectives1 To provide long-term outcome evidence for the prevention and treatment of ONFH by TCM,a retrospective cohort study on convalescent SARS patients diagnosed with steroid-induced ONFH was conducted to evaluate the long-term effect of HGF treatment.2 To provide research methods and baseline reference for the next-step study regarding the bone repair process after HGF treatment,we reconstructed the femoral head model based on CT images.Then we analyzed the femoral head’s structure components based on the Hounsfield Unit(HU)information.Especially,the time dimension of the disease course was analyzed to explore the natural evolution of osseous structure and collapse risk during the development of ONFH.3 To clarify the effect of TCM on the osseous structure and collapse risk during the bone repair process,we continuously and intensively observe the changes in the osseous structure of ONFH after HGF treatment,by using CT image-based method for osseous structure analysis of femoral head.MethodsPart 1 The long-term effect of Huo-Gu Formula treatment for steroid-induced osteonecrosis of femoral head among convalescent SARS patientsThis study included 33 patients who received glucocorticoid treatment during SARS infection in 2003 and subsequently developed steroid-induced ONFH.Then they were administrated with HGF treatment for ONFH in our hospital.There were nine males and 24 females,with a mean age of 42.52±8.26 years.All patients suffered from bilateral affected ONFH(66 hips).According to the ARCO staging system,ten hips were ARCO stage Ⅰ lesions,43 hips were ARCO stage Ⅱ lesions,nine hips were ARCO stage Ⅲ lesions,and four hips were ARCO stage Ⅳ lesions.All patients received oral HGF treatment for at least six months.All patients are continuously followed up every year until November 2019.Face-to-face interviews,electronic questionnaires,and medical imaging examinations were used for the final follow-up evaluation.The primary outcome measure was the incidence of total hip arthroplasty(THA).The secondary outcome measures included Harris hip score scale(HHS scale),walking function index of the core outcome set for ONFH,the incidence of femoral head collapse,Kellgren-Lawrence osteoarthritis classification(KL classification).Part 2 The dynamic evolution of osseous structure and collapse risk in osteonecrosis of femoral head:preliminary CT image analysisFrom the year 2014 to 2019,the present study included 50 patients with ONFH(50 studied hips)who underwent medical imaging follow-up.There were 28 males and 22 females,with a mean age of 38.12±10.14 years.Two sets of CT images(DCM format files)with an interval of 12 months were obtained.According to the first CT image series,29 hips were ARCO stage Ⅱ lesions,21 hips were ARCO stage Ⅲ A lesions,and the mean modified Kerboul angle was 285.24±36.40°.The second CT image series was used to evaluate radiographic progression,including the new occurrence or new exacerbation of femoral head collapse within 12 months.Also,five normal hip joints were selected as normal controls.Based on the first series of CT images,50 femoral head models were reconstructed using the medical image processing software Mimics Medical 21.0.According to the different HU thresholds of compact bone and soft tissue,different tissue structures were separated and reconstructed,and then their volumes were observed and measured.The density of specific part of an organ can be calculated based on the tissue HU data.After the femoral head model’s meshing process in the 3-matic Medical 13.0 software,the bone mineral density(BMD)of the femoral head was calculated through the material assignment process.The disease course from the appearance of hip symptoms to the first CT examination was included for linear regression analysis with sclerotic bone volume,soft tissue volume,and BMD.Besides,the logistic analysis was used to explore the correlation between bone structure indexes and radiographic progression.The performance of bone structure indexes to predict radiographic progression was evaluated through Receiver Operating Characteristic Curve(ROC curve)analysis.Part 3 Intensive follow-up of osseous structure evolution and collapse risk after Huo-Gu Formula treatment for osteonecrosis of femoral headFrom 2016 to 2019,the present study included ONFH patients who received regular and intensive follow-up after HGF treatment.Patients were divided into the Stable group and the Progressive Group with 20 studied hips in each group,according to the occurrence of radiographic progression within 12 months after HGF treatment.Radiographic progression referred to the new occurrence or new exacerbation of femoral head collapse within 12 months.According to the pre-treatment CT images,24 hips were ARCO stage Ⅱ lesions,16 hips were ARCO stage ⅢA lesions,and the mean modified Kerboul angle was 287.11±24.70°.All hips underwent four times of CT scans with an interval of 4 months.All included hips were continuously and intensively followed-up for 12 months.Based on CT images(DCM format files),a total of 160 femoral head models were reconstructed using medical image processing software Mimics Medical 21.0.According to the difference in HU threshold between compact bone and soft tissue,the femoral head’s sclerotic bone and soft tissue were automatically segmented.Then the solid models were reconstructed,and the volumes were observed and measured.After the meshing process of the femoral head model in the 3-matic Medical 13.0 software,the BMD of the femoral head was measured through the material assignment process.Based on the continuous and intensive observation of multiple time-point data,the differences in sclerotic bone volume,soft tissue volume,and BMD between the two groups,as well as the dynamic evolution differences,were analyzed.Logistic analysis was used to explore the correlation between the early changes in osseous structure indexes and the radiographic progression after HGF treatment.Furthermore,through ROC curve analysis,we evaluated the performance of these indexes in predicting the radiographic progression.ResultsPart 1 The long-term effect of Huo-Gu Formula treatment for steroid-induced osteonecrosis of femoral head among convalescent SARS patientsThe mean follow-up duration of this study was 14.88±2.25 years.At the final follow-up,five hips were converted to THA.The conversion rate of THA was 7.57%.Kaplan-Meier survival analysis found that the estimated hip survival time was more than 15 years on average.The Log-rank test found that the hip survival time in ARCO stage IVwas significantly shorter than those in other stages(P<0.05).Of the 53 pre-collapse hips,14 hips had progressed to femoral head collapse,with a collapse rate of 26.41%.Of all 66 hips,38 hips developed osteoarthritis(KL level 2 or severer).The incidence of osteoarthritis was 57.57%.In 28 patients who were not converted to THA,the mean HHS was 63.89±10.30.The HHS index was then divided into pain index(44 points in total)and physical function index(56 points in total)for detailed analysis.The average pain index was 24.29±8.35 points,which corresponded to a medium level(45%)of pain according to the computing method of the visual analogue scale.The average physical function index was 39.61±5.59,which corresponded to the fact that 70%of physical function was preserved.Pain was an important factor in the loss of HHS scores in this patient cohort.Kendall’s tab correlation analysis found no correlation between HHS-pain index and K-L classification(P>0.05).Part 2 The dynamic evolution of osseous structure and collapse risk in osteonecrosis of femoral head:preliminary CT image analysisAccording to morphological observation,the osseous structure of the normal femoral head is generally composed of cancellous bone and bone marrow(in soft tissue properties),while the necrotic femoral head has the following characteristics:①The necrotic lesion is often a mixed structure of sclerotic bone,cancellous bone,and structure in soft tissue properties;②The appearance of sclerotic bone is an important feature for antidiastole from the normal femoral head,and it tends to form the boundary of the necrotic lesion,but the distribution of sclerotic bone is usually fractured and irregular;③The volume of soft tissue is reduced in the necrotic lesion,and changes of soft tissue can also be observed in the normal osseous structure outside the necrotic lesion.After incorporating the time dimension of the disease course for linear regression analysis,the present study found that the disease course had a linear regression relationship with sclerotic bone volume,soft tissue volume,and BMD(P<0.05).The regression coefficients were 126.424,-144.674,and 0.005,respectively.These results suggested that the sclerotic bone volume and BMD increased with the disease course,and the soft tissue volume decreased with the disease course.Meanwhile,the R2 values of sclerotic bone volume,soft tissue volume,and BMD were 0.441,0.088,and 0.199,respectively,suggesting that their evolution patterns were affected not only by the disease course.Logistic regression analysis found that sclerotic bone volume and BMD were significant correlation factors of radiographic progression(P<0.05).The increase in BMD is accompanied by a decrease in the collapse risk(OR<0.001).The Logistic regression equation integrating BMD and sclerotic bone volume could be used to calculate the collapse index,which was of prediction value for the radiographic progression(A UC=0.765,P<0.05).Part 3 Intensive follow-up of osseous structure evolution and collapse risk after Huo-Gu Formula treatment for osteonecrosis of femoral headAccording to the morphological observation,sclerotic bone is an important feature observed in femoral heads from both groups.In the Stable Group,the contour line of the femoral head at each follow-up time-point remained even,and the volume of sclerotic bone showed a dynamically growing trend.In the Progressive Group,the contour line of the femoral head at each time-point gradually became disordered and twisted,and the volume of sclerotic bone was still growing dynamically.Based on visual impressions,we conducted a quantitative comparison between the two groups.According to the overall analysis of 160 femoral head models,the volume of sclerotic bone at each time-point was always larger than that of the adjacent late time point(P<0.05).Compared with the Progress Group,we observed stronger BMD in the Stable Group at the three consecutive time points after HGF treatment(P<0.05).During the period 0～4 months,4～8 months,and 0～12 months,there was statistical significance in the amount of sclerotic bone volume growth between the two groups(P<0.05),while the amount of sclerotic bone volume growth during the period 8～12 months tended to be statistically different between the two groups(P=0.068).Generally,within 12 months after HGF treatment,the increase of sclerosis bone volume per unit time in the Stable Group consistently exceeds that in the Progressive Group.Logistic regression analysis found that the early changes in osseous structure,including the growth rate of sclerotic bone volume during the first four months and the BMD at the fourth month after HGF treatment,were significantly correlated with radiographic progression(P<0.05),with the OR values at 0.088 and<0.001,respectively.These low OR values suggested that the growths in sclerotic bone volume and BMD are protective factors to prevent radiographic progression.The Logistic regression equation integrating these two osseous structure evolution indexes was used to calculate the collapse index.The collapse index was proved with satisfactory performance in predicting radiographic progression(AUC=0.850,P<0.05).Conclusions1 The present study suggested a positive long-term effect of HGF treatment for steroid-induced ONFH among convalescent SARS patients.HGF treatment helps prevent femoral head collapse,delay THA,and maintain physical function.2 The osseous structure of ONFH is dynamically evolving with the disease course,and this process is accompanied by dynamic changes in the risk of femoral head collapse.3 The dynamically precise follow-up observation of the osseous structure evolution reveals the effect of HGF treatment on accelerating and promoting the bone repair process,which is closely associated with the effect of collapse prevention.