Protective Effect of Human Umbilical Cord Mesenchymal Stem Cells in Glucocorticoid-induced Osteonecrosis of Femoral Head

Objective:To evaluate the effect of human umbilical cord mesenchymal stem cells(hUC-MSCs)on preventing rats from glucocorticoid-induced osteonecrosis of femoral head(GC-ONFH)in the early stage in vivo and to investigate the possible mechanism of hUC-MSCs in regulating the balance of osteogenesis and adipogenesis.Methods:All rats were randomly divided into 3 groups:control group(C group),model group(M group),and intervention group(Ⅰ group).The model of GC-ONFH was developed by a sequential administration of lipopolysaccharide and methylprednisolone.The rats in the Ⅰ group were treated with caudal vein injection of hUC-MSCs.Six weeks later,the blood samples were obtained to measure the activity of alkaline phosphatase(ALP)and the content of triglyceride(TG)in serum,and the femoral heads were harvested and observed by hematoxylin-eosin staining,Micro-CT,Western blot and real-time quantitative polymerase chain reaction.Results:After intervention of hUC-MSCs,the necrosis rate of femoral head decreased from 83%(10/12)to 33%(4/12),the rate of empty bone lacuna was significantly decreased,the activity of ALP increased significantly,the content of TG decreased significantly,the bone density increased obviously,the expression of RUNX2 and Col Ⅰ increased significantly and the expression of PPARγ decreased significantly.Conclusion:These results revealed that caudal vein injection of hUC-MSCs can effectively reduce the incidence of GC-ONFH in rats by increasing ALP activity and reducing TG content in serum,increasing bone mineral density,promoting the expression of RUNX2 and Col I,and inhibiting the expression of PPARγ.

Effects of individual shock wave therapy vs celecoxib on hip pain caused by femoral head necrosis

BACKGROUND Celecoxib has been used to treat hip discomfort and functional difficulties associated with osteonecrosis of the femoral head(ONFH),although significant adverse reactions often follow long-term use.Extracorporeal shock wave therapy(ESWT)can delay the progression of ONFH,alleviate the pain and functional limitations it causes,and avoid the adverse effects of celecoxib.AIM To investigate the effects of individual ESWT,a treatment alternative to the use of celecoxib,in alleviating pain and dysfunction caused by ONFH.METHODS This was a randomized,controlled,double-blinded,non-inferiority trial.We examined 80 patients for eligibility in this study;8 patients were excluded based on inclusion and exclusion criteria.A total of 72 subjects with ONFH were randomly assigned to group A(n=36;celecoxib+alendronate+sham-placebo shock wave)or group B(n=36;individual focused shock wave[ESWT based on magnetic resonance imaging three-dimensional(MRI-3D)reconstruction]+alendronate).The outcomes were assessed at baseline,at the end of treatment,and at an 8-wk follow-up.The primary outcome measure was treatment efficiency after 2 wk of intervention using the Harris hip score(HHS)(improvement of 10 points or more from the baseline was deemed sufficient).Secondary outcome measures were post-treatment HHS,visual analog scale(VAS),and Western Ontario and McMaster Universities Osteoarthritis Index(WOMAC)scores.RESULTS After treatment,the pain treatment efficiency of group B was greater than that of group A(69%vs 51%;95%CI:4.56%to 40.56%),with non-inferiority thresholds of-4.56%and-10%,respectively.Furthermore,the HHS,WOMAC,and VAS scores in group B dramatically improved during the follow-up period as compared to those in group A(P<0.001).After therapy,the VAS and WOMAC in group A were significantly improved from the 2nd to 8th wk(P<0.001),although HHS was only significantly altered at the 2 wk point(P<0.001).On the 1st d and 2nd wk after treatment,HHS and VAS scores were different between groups,with the difference in HHS lasting until week 4.Neither group had severe complications such as skin ulcer infection or lower limb motorsensory disturbance.CONCLUSION Individual shock wave therapy(ESWT)based on MRI-3D reconstruction was not inferior to celecoxib in managing hip pain and restrictions associated with ONFH.

Lithium chloride prevents glucocorticoid-induced osteonecrosis of femoral heads and strengthens mesenchymal stem cell activity in rats

Background:Accumulating evidence suggests that lithium influences mesenchymal stem cell(MSC)proliferation and osteogenic differentiation.As decreased bone formation in femoral heads is induced by glucocorticoids(GCs),we hypothesized that lithium has a protective effect on GC-induced osteonecrosis of femoral heads(ONFH).Methods:A rat ONFH model was induced by methylprednisolone(MP)and the effect of lithium chloride on the models was evaluated.Micro-computed tomography(CT)-based angiography and bone scanning were performed to analyze the vessels and bone structure in the femoral heads.Hematoxylin and eosin and immunohistochemical staining were performed to evaluate the trabecular structure and osteocalcin(OCN)expression,respectively.Bone marrow-derived MSCs were isolated from the models,and their proliferative and osteogenic ability was evaluated.Western blotting and quantitative real-time polymerase chain reaction were performed to detect osteogenic-related proteins including Runx2,alkaline phosphatase,and Collagen I.Results:Micro-CT analysis showed a high degree of osteonecrotic changes in the rats that received only MP injection.Treatment with lithium reduced this significantly in rats that received lithium(MP+Li group);while 18/20 of the femoral heads in the MP showed severe osteonecrosis,only 5/20 in the MP+Li showed mild osteonecrotic changes.The MP+Li group also displayed a higher vessel volume than the MP group(0.2193 mm3vs.0.0811 mm3,P<0.05),shown by micro-CT-based angiography.Furthermore,histological analysis showed better trabecular structures and more OCN expression in the femoral heads of the MP+Li group compared with the MP group.The ex vivo investigation indicated higher proliferative and osteogenic ability and upregulated osteogenic-related proteins in MSCs extracted from rats in the MP+Li group than that in the MP group.Conclusions:We concluded that lithium chloride has a significant protective effect on GC-induced ONFH in rats and that lithium also enhances MSC proliferation and osteogenic differentiation in rats after GC administration.

Finite Element Analysis on the Diagnosis and Treatment of Osteonecrosis of Femoral Head

Developing the radiographic images from two to three-dimensional, finite element analysis(FEA) technology can set up the model, predicting diagnosis, treatment design, as well as surgical plan. FEA provides an accurate three-dimensional finite element biomechanical study in osteonecrosis of femoral head(ONFH). The papers in the latest 5 years related to femoral head osteonecrosis and finite element analysis application are concentrated on. We summarize the latest research progress and problems, including the applied research carried out in the femoral head osteonecrosis clinical cases,innovational skills, so as to point out the direction of future research in FEA.

Three-dimensional finite element analysis on the treatment of adult femoral head necrosis using different graft

Objective： To study the alternation of distribution of the stress in the necrotic femoral head with different kinds of grafting materials by using three-dimensional element methods and find out the most optimal one with sound biomechanical principles before clinical application. Methods： We prepared a three dimension finite element model of central femoral head necrosis with surface modeling technique （spiral ct）and calculated the peak stress index of necrotic portion in three situations：core drilling in 14 mm diameter and grafting with titanium, fibula, polylactide. Results： The peak stress index of normal femoral head was 0.05, but in osteonecrotic femoral head, the peak stress index was 13 times of the normal （0.67）. The value of necrotic portion with big shallow angle （0.67） was larger than the one with small deep angle （0.49）. Core drilling in 14 mm diameter and grafting with titanium, fibula and polyactide could diminish the bad stress in the necrotic portion respectirdy. The decrease volume in small necrotic area （90°） is marked（38% ）, while in big necrotic area （150°） it was indistinctive（ 10% ）. In the same necrotic portion,the decrease volume with titanium was（38% ） larger than with the fibula （37%）, and also larger than with the polyactide（29% ）. Conclusion： In necrotic portion of femoral head, the badshess could produce 13 times of the normal one. Grafting with titanium, fibula and polyactide could reduce the bad stress respectively. The effect of titanium is most marked, second is fibula and polyactide is indistinctive. The effect was in big necrotic portion is bad, the best effect was in small necrotic portion.

Research Progress of Tonifying Kidney and Promoting Blood Circulation in the Treatment of Steroid-induced Necrosis of Femoral Head

Osteonecrosis of the femoral head is a common disability disease of the hip joint in China,and osteonecrosis of the femoral head caused by hormone factors is the most common,which is related to the gradual increase in the utilization rate of glucocorticoids in recent years.It is a refractory disease in orthopaedics with a poor prognosis.For this disease,the treatment of traditional Chinese medicine has certain advantages.In view of this,the author reads,analyzes and summarizes its materials by searching China Journal full-text Database and Wanfang Database.This paper reviews the mechanism and clinical research progress of tonifying kidney and activating blood circulation in the prevention and treatment of steroid-induced osteonecrosis of the femoral head,hoping to provide help for the clinical treatment of hormone-related osteonecrosis of the femoral head.

EXPERIMENTAL STUDY ON FREE VASCULARIZED FIBULA GRAFTING IN REVASCULARIZING FEMORAL HEAD

laterals or femoral head and neck of 18 mature healthy male domestic dogs were divided into two groups by the principle or auto-control.Avascular osteonecrosis of femoral head(ONFH)and old femoral neck fracture(FNF)were made respectively.Free vascularized fibula grafting was performed 2 weeks later.Arter operation, X-ray,histopathological,electron microscopic,tetracycline fluorescence labelling and99mTc-methylene diphosphorate scanning were carried out respectively.The result indicated that free vascularized fibula grarting could provide new blood supply system to injured femoral head and participate in the repairing process of avascular uecrosis of femoral head.

Glucocorticoids affect the metabolism of bone marrow stromal cells and lead to osteonecrosis of the femoral head： a review

Objective To review the recent developments in the mechanisms of glucocorticoids induced osteonecrosis of femoral head （ONFH） and introduce a new theory of ONFH.Data sources Both Chinese- and English-language literatures were searched using MEDLINE （1997-2011）,Pubmed （1997-2011 ） and the Index of Chinese-language Literature （1997-2011 ）.Study selection Data from published articles about mechanisms of glucocorticoids induced ONFH in recent domestic and foreign literature were selected.Data extraction Data were mainly extracted from 61 articles which are listed in the reference section of this review.Results Glucocorticoids are steroid hormones secreted by the adrenal cortex that play a pivotal role in the regulation of a variety of developmental,metabolic and immune functions.However,high dose of exogenous glucocorticoids usage is the most common non-traumatic cause of ON FH.Glucocorticoids can affect the metabolisms of osteoblasts,osteoclasts,bone marrow stromal cells and adipocytes which decrease osteoblasts formation but increase adipocytes formation and cause ONFH finally.Conclusions Glucocorticoids affect the differentiation of mesenchymal stem cells,through activating or inhibiting the related transcript regulators of osteogenesis and adipogenesis.At last,the size and volume of mesenchymal stem cells derived adipocytes will increase amazingly,but the osteoblasts will be decreased obviously.In the meantime,the activity of the osteoclasts will be activated.So,these mechanisms work together and lead to ONFH.

Corticosteroid-induced Osteonecrosis of the Femoral Head:Detection,Diagnosis,and Treatment in Earlier Stages

Objective： This review aimed to provide a current recommendation to multidisciplinary physicians for early detection, diagnosis, and treatment of corticosteroid-induced osteonecrosis of the femoral head （ONFH） based on a comprehensive analysis of the clinical literature. Data Sources： For the purpose of collecting potentially eligible articles, we searched for articles in the PubMed, Cochrane Library, Embase, and CNKI databases up to February 2017, using the following key words： ＆quot;corticosteroid＆quot;, ＆quot;osteonecrosis of the femoral head＆quot;,＆quot;risk factors＆quot;, ＆quot;diagnosis＆quot;, ＆quot;prognosis＆quot;, and ＆quot;treatment＆quot;. Study Selection： Articles on relationships between corticosteroid and ONFH were selected for this review. Articles on the diagnosis, prognosis, and intervention of earlier-stage ONFH were also reviewed. Results： The incidence of corticosteroid-induced ONFH was associated with high doses of corticosteroids, and underlying diseases in certain predisposed individuals mainly occurred in the first 3 months of corticosteroid prescription. The enhanced awareness and minimized exposure to the established risk factors and earlier definitive diagnosis are essential for the success of joint preservation. When following up patients with ONFH, treatment should be started if necessary. Surgical treatment yielded better results than conservative therapy in earlier-stage ONFH. The ideal purpose of earlier intervention and treatment is permanent preservation of the femoral head without physical restrictions in daily living. Conclusions： Clinicians should enhance their precaution awareness of corticosteroid-induced ONFH. For high-risk patients, regular follow-up is very important in the 1st year after high-dose prescription of corticosteroids. Patients with suspected ONFH should be referred to orthopedists for diagnosis and treatment in its earlier stage to preserve the joint.

A modified technique of bone grafting pedicled with femoral quadratus for alcohol-induced osteonecrosis of the femoral head

Background Quadratus femoris pedicled bone grafting has yielded satisfactory long-term clinical outcome for osteonecrosis of the femoral head （ONFH） in pre-collapse ONFH without extensive lesion. However, for pre-collapse ONFH with extensive necrotic area, it is still challenging to preserve the femoral head. The current study aimed to introduce a new technique of deliquesce strut with titanium mesh containing bone grafting pedicled with the femoral quadratus and to evaluate its short-term outcomes.Methods From January 2008 to December 2008, 10 ONFH patients （12 hips） underwent operations by a new technique of deliquesce strut with titanium mesh containing bone grafting pedicled with the femoral quadratus （group A）.According to the ARCO classification system, there were two hips in stage Ⅱ B and 10 hips in stage Ⅱ C. Also in the same period, 12 ONFH patients （16 hips） underwent operations by the conventional procedure of quadratus femoris pedicled bone grafting （group B）. There were 6 hips in stage Ⅱ B and 10 hips in stage Ⅱ C. All patients were males and suffered from alcohol induced ONFH. For the new technique, the necrotic area was evaluated, and a titanium mesh piece of the same size （range from 2.5 cm×2.8 cm to 2.8 cm×3.4 cm） was obtained and shaped to match the contour of the head. The cancellous bone was first placed underneath the subchondral bone and was densely impacted （about 1 to 2 mm thick）.Then the titanium mesh piece was inserted. The length of the decompressive trough was measured. A titanium cylinder mesh cage with a diameter of 1.6 cm of the same length was obtained, with a ＂U＂ shaped window in the wall being created to make room for the muscle pedicle. The muscle pedicle bone was inserted into the titanium mesh cage to form a bone graft-titanium cage complex and, then the complex was inserted. The hundred percent score method was used for outcome evaluation. Clinical and radiographic outcomes were compared between group A and group B.Results The average operative time was 150 minutes （130 to 185 minutes） in group A, with an average of 130 minutes （120 to 180 minutes） in group B. The mean blood loss was 400 ml （300 to 500 ml） in group Aand 350 ml （250 to 500 ml）in group B. Group A patients were followed up for an average of 19.2 months （14 to 24 months）, with an average of 18.5 months （12 to 24 months） for Group B. Full weight bearing was allowed 5 to 7 months postoperatively. Pain and function were obviously improved. For group A, pain score improved from a mean of 9.8 points preoperatively to an average of 24.6 points postoperatively, and function score improved from a mean of 9.0 points preoperatively to an average of 17.4 points postoperatively. In group B, pain score improved from a mean of 9.5 points preoperatively to an average of 24.2 points postoperatively and function score improved from a mean of 9.2 points preoperatively to an average of 17.2 points postoperatively. The range of motion changed the least, with score improvement from a preoperative mean of 13.9 points to postoperative 16.8 points for group A and from a preoperative mean of 13.7 points to postoperative 16.5 points for group B. Radiographic score improved from preoperative 31 points to postoperative 38 points for group A, in comparison with an improvement from preoperative 31 points to postoperative 37 points for group B. At the latest follow up, 11 hips were rated as excellent and 1 hip was better for group A, with 14 hips being rated as excellent and 2 hips being better in group B. There was no statistically significant difference between groups A and B in clinical and radiographic outcomes.Conclusion For ONFH in stage ARCO llC, satisfactory clinical outcome can be achieved by the new technique in the short-term period while the long-term clinical outcome has yet to be determined.

Effects of HuoguⅠFormula(活骨Ⅰ方) on Correlated Factors of Bone Regeneration in Chickens with Steroid-Induced Necrosis of Femoral Head

Objective： To study the mechanism of Huogu I Formula （活骨I方） in treating osteonecrosis of femoral head. Methods： Forty-eight healthy female Leghorn chickens were randomly divided into control group, model group and Huogu I group, and each group consisted of 16 chickens. At the meantime of model establishment, chickens of the Huogu I group were administrated with decoction, while the model and control group with distilled water by gavage. At the 8th and 16th week after medication, blood samples were obtained for blood lipid detection while both sides of femoral head were harvested for the rest of examinations. Specifically, expressions of bone morphogenetic protein-2 （BMP2）, transforming growth factor beta1 （TGFβ1）, Smad4 and Smad7 were evaluated by immunohistochemistry, while expression of osteoprotegerin/receptor activator of nuclear factor kappaB ligand （OPG/RANKL） mRNA was detected by in situ hybridization. Results： Compared with the control group, serum levels of total cholesterol （TG）, triglyceride （TG） and low-density lipoprotein cholesterol （LDL-C） in the model group rose significantly. Positive cell counting of BMP2, TGF 131, Smad4 and OPG in femoral head of the model group dropped prominently. Positive cell counting of Smad7 and RANKL increased dramatically. In contrast with the model group, levels of TC, TG and LDL-C in Huogu I group reduced significantly. Positive cell counting of BMP2, TGFβ1, Smad4 and OPG in femoral head of the Huogu I group increased prominently. Indices of Smad7 and RANKL both decreased significantly. Especially at the 8th week, these variations were more significant. Conclusion： Huogu I Formula is effective in promoting repair of necrotic femoral head by regulating the expressions of BMP2, TGFβ1, Smads and OPG/RANKL of osteoclast in femoral head.