Garida Zhao

Radiological outcome analysis of transtrochanteric curved varus osteotomy for osteonecrosis of the femoral head at a mean follow-up of 12.4 years

We investigated the factors related to the radiological outcome of a transtrochanteric curved varus osteotomy in patients with osteonecrosis of the hip. We reviewed 73 hips in 62 patients with a mean follow-up of 12.4 years (5 to 31.1). There were 28 men and 34 women, with a mean age of 33.3 years (15 to 68) at the time of surgery. The 73 hips were divided into two groups according to their radiological findings: group 1 showed progression of collapse and/or joint-space narrowing; group 2 had neither progressive collapse nor joint-space narrowing. Both of these factors and the radiological outcomes were analysed by a stepwise discriminant analysis. A total of 12 hips were categorised as group 1 and 61 as group 2. Both the post-operative intact ratio and the localisation of the necrotic lesion correlated with the radiological outcome. The cut-off point of the postoperative intact ratio to prevent the progression of collapse was 33.6%, and the cut-off point to prevent both the progression of collapse and joint-space narrowing was 41.9%. The results of this study indicate that a post-operative intact ratio of 33.0% is necessary if a satisfactory outcome is to be achieved after this varus osteotomy.

Bone and cartilage metabolism markers in synovial fluid of the hip joint with secondary osteoarthritis

OBJECTIVE The aim of this study was to compare the levels of bone and cartilage metabolism markers in the synovial fluid of the hip joint between patients with secondary OA due to osteonecrosis of the femoral head (ONFH), rapidly destructive arthrosis (RDA) and developmental dysplasia of the hip (DDH). METHODS We studied 70 synovial fluid samples obtained from 57 patients with ONFH (mean age 46 years, 34 males, 23 females), 21 samples obtained from 21 patients with RDA (mean age 70 years, 2 males, 19 females) and 20 samples obtained from 20 patients with DDH (mean age 56 years, 2 males, 18 females). The levels of bone alkaline phosphatase (BAP) and tartrate-resistant acid phosphatase 5b (TRACP-5b), as bone metabolism markers, and matrix metalloproteinase 3 (MMP-3) and keratan sulphate (KS), as cartilage metabolism markers, were analysed. RESULTS The levels of BAP, MMP-3 and KS were significantly higher in the ONFH group than in the RDA and DDH groups. The levels of TRACP-5b were highest in the RDA group. The levels of BAP in the ONFH group after the development of osteoarthritic changes were significantly lower than those observed in earlier stages. In comparisons between the samples obtained from each group with a terminal condition, the ONFH samples exhibited significantly higher MMP-3 and KS levels, while the TRACP-5 levels were highest in the RDA group. CONCLUSION The ONFH patients showed a relatively bone formative condition before the osteoarthritic stage and maintained a higher rate of cartilage turnover throughout several stages compared with the RDA and DDH patients. RDA patients were characterized by a significantly high osteoclast activity.

Effects of an anti-platelet drug on the prevention of steroid-induced osteonecrosis in rabbits

OBJECTIVE To investigate the effects of an anti-platelet drug (clopidogrel) on the prevention of steroid-induced osteonecrosis (ON) in rabbits. METHODS Adult male Japanese white rabbits were divided into two groups and treated as follows: one group received daily clopidogrel mixed in normal saline (AP; n = 35), the other received only normal saline (NS; n = 30). One week after the administration, all rabbits were injected once intramuscularly with 20 mg/kg of methylprednisolone acetate into the right gluteus medius muscle. Three weeks after, both the femora and humeri were examined histopathologically for the presence of ON. The platelet aggregation assay and hematological examinations were performed before and after the steroid injection. RESULTS The incidence of ON in the AP group (48.5%) was significantly lower than that observed in the NS group (73.3%). The platelet aggregations in the AP group were significantly inhibited by the administration of clopidogrel. The levels of total cholesterol and triglycerides showed no significant differences between the AP and NS group. CONCLUSION The present experimental study demonstrated that the administration of an anti-platelet drug prevented steroid-induced ON in rabbits and that platelet aggregation seems to be one of the possible factors involved in the pathogenesis of steroid-induced ON.

Preventive effects of the anti-vasospasm agent via the regulation of the Rho-kinase pathway on the development of steroid-induced osteonecrosis in rabbits

A number of studies have suggested that ischemia is the principal pathomechanism of osteonecrosis, however, the detailed mechanism responsible for ischemia remains unclear. We examined the effects of fasudil, an anti-vasospasm agent, on the development of steroid-induced osteonecrosis in rabbits. One group of rabbits received 15mg/kg of fasudil intravenously, which were then injected once intramuscularly with 20mg/kg of methylprednisolone (n=33), and one received methylprednisolone alone as a control (n=28). Eight rabbits from each group were sacrificed 24h after methylprednisolone injection to analyze them by the expression of endothelinA-receptor and eNOS. Two weeks after the steroid injection, the femora and humeri were examined histopathologically for the incidence of osteonecrosis. In addition, plasma from each of four osteonecrosis-positive or -negative rabbits was used for the proteomic analysis in the fasudil group. The incidence of osteonecrosis was significantly lower in the fasudil group (32%) than that in the control group (75%) (P<0.01). Immunohistochemically, endothelinA-receptor expressions levels were decreased in the smooth muscle of the bone marrow in the fasudil group in comparison to that in the control group. The eNOS expressions levels in both serum and bone marrow in the MF group were significantly higher than those in the M group (P<0.05). Based on the proteomic analysis, several proteins related to vasospasm, such as fibrinogen, thrombin, and apolipoprotein E, were identified in rabbits with osteonecrosis soon after steroid administration. This study indicates that vasospasm is one of the important factors involved in the pathogenesis of steroid-induced osteonecrosis and that the anti-vasospasm agents seem to decrease the incidence of steroid-induced osteonecrosis.

Lipid metabolism abnormalities in alcohol-treated rabbits: a morphometric and haematologic study comparing high and low alcohol doses

The pathogenesis of alcohol‐induced osteonecrosis remains unclear. The purpose of the present study was to evaluate the morphological changes in bone marrow fat cells and the changes in the serum lipid levels in alcohol‐treated rabbits. Fifteen rabbits were randomly assigned into three groups: Four rabbits intragastrically received low‐dose alcohol (LDA) (15 ml/kg per day) containing 15% ethanol for 4 weeks, five rabbits received high‐dose alcohol (HDA) (30 ml/kg per day) for 4 weeks and six rabbits received physiologic saline for 4 weeks as a control group. Six weeks after the initial alcohol administration, all rabbits were sacrificed. The mean size of the bone marrow fat cells in rabbits treated with HDA was significantly larger than that in the control group (P = 0.0001). Haematologically, the levels of triglycerides and free fatty acids in the rabbits treated with both low‐dose and HDA were significantly higher than those in the control group (P = 0.001 for both comparisons). The results of this study are that there are lipid metabolism abnormalities, both morphologically and haematologically, after alcohol administration. Also these findings were more apparent in rabbits treated with HDA than those treated with LDA.

Cholesterol- and lanolin-rich diets may protect against steroid-induced osteonecrosis in rabbits

Background and purpose It remains controversial how hypercholesterolemia influences the development of steroid-induced osteonecrosis (ON). We investigated the role of hypercholesterolemia induced by a cholesterol-rich diet on the development of ON in rabbits. Methods 40 adult male Japanese white rabbits were randomly divided into 2 groups. 20 rabbits were maintained on a cholesterol-rich diet for 2 weeks before receiving steroid treatment (the CHOL group). The other 20 rabbits were maintained on a standard diet (the control (CTR) group). 2 weeks after the start of the study, all 40 rabbits were injected with methylprednisolone acetate (MPSL) into the right gluteus medius muscle (20 mg/kg body weight). 2 weeks after the steroid injection, both the femora and humeri were examined histopathologically for the presence of ON. Hematological analysis of the serum lipid levels was performed every week. Based on the same protocol, we also investigated the effects of lanolin, a primary component of a cholesterol-rich diet, in another group (the LA group). Results The incidence of ON in the CHOL group (3/20) was lower than that observed in the CTR group (15/20) (p < 0.001). During the whole experiment, the levels of total cholesterol and the ratio of low-density lipoprotein to high-density lipoprotein in the CHOL group were higher than those observed in the CTR group (p < 0.001). The LA group also had a lower incidence of ON (2/20), and the lipid levels in the LA group showed similar changes to those observed in the CHOL group. Interpretation Our findings suggest that preexisting hypercholesterolemia itself induced by a cholesterol-rich diet does not increase the risk of developing steroid-induced ON, but rather seems to diminish it. Lanolin may be the active anti-ON component of the cholesterol diet.

Cytochrome P4503A activity affects the gender difference in the development of steroid-induced osteonecrosis in rabbits

The aim of this study was to investigate cytochrome P4503A activity and its correlation with the development of osternecrosis (ON) among male and female steroid‐treated rabbits. Forty adult rabbits (male, n = 20; female, n = 20) were injected once with 20 mg/kg of methylprednisolone intramuscularly. Haematologically, cytochrome P4503A activity was measured by plasma 1′‐hydroxymidazolam‐to‐midazolam (1′‐OH‐MDZ/MDZ) ratio just before and 48 h after the steroid injection. We also measured the levels of oestradiol every week. Both femora and humeri were histopathologically examined for the presence of ON. Fifteen of 20 male rabbits (75%) developed ON, while 6 of 20 female rabbits (30%) did so. There was a significant difference in the rate of incidence of ON between male and female rabbits (P = 0.010). The 1′‐OH‐MDZ/MDZ ratio in female rabbits just before, as well as 48 h after the steroid injection was significantly higher than that in male rabbits (P = 0.039 and P = 0.001 respectively). In addition, 1′‐OH‐MDZ/MDZ ratio in female rabbits significantly increased in 48 h after the steroid injection (P = 0.044), while that in male rabbits did not so (P = 0.978). The levels of oestradiol in female rabbits were significantly higher than those in male rabbits during the experimental period (P = 0.008). In conclusion, this study indicates that the gender difference in cytochrome P4503A activity may be one of the important factors for the development of steroid‐induced ON, possibly due to the effects of oestradiol.

Osteonecrosis of the femoral head extending into the femoral neck

Osteonecrosis of the femoral head (ONFH) is an ischemic disorder that can lead to femoral head collapse and secondary osteoarthritis. Although the condition is usually limited to the femoral head, we report a rare case of biopsy-proven ONFH extending into the femoral neck, which required hip replacement surgery. We emphasize the imaging features of this condition and briefly discuss its potential relevance.

Authors’ Reply: Letter to the Editor

We appreciate the thoughtful comments from Drs. Jaffré and Rochefort. Clinically, osteonecrosis (ON) of the femoral head has been proven to be associated with steroid treatment and alcohol abuse (Hirota et al. 1993; Mont et al. 1995; Fukushima et al. 2010). In addition, previous reports suggested that the pathological changes observed in both steroidand alcohol-induced ON are similar (Glimcher et al. 1979; Solomon 1985; Mont et al. 1995). In the field of animal models of osteonecrosis, steroid-induced ON has already been established in rabbits (Yamamoto et al. 1997; Miyanishi et al. 2002). However, we believe that a model of alcohol-induced ON has not yet been established, although some reports have described the bone marrow changes (Solomon 1985; Wang et al. 2003). Regarding steroid-induced ON in rabbits, previous studies have confirmed that a single injection of high-dose corticosteroid induces ON 2 weeks after injection (Motomura et al. 2004; Nishida et al. 2008; Ikemura et al. 2010). Therefore, our hypothesis in this study was that a short period of high-dose alcohol administration might produce ON in the early periods, similar to the observations in steroid-induced ON models. Drs. Jaffré and Rochefort have commented on three important issues. Firstly, they comment about the quantity of alcohol administered. Following the article described by Wang et al. (spirits, containing 45% ethanol; 4.5 ml ⁄ kg ⁄ day in 100% ethanol equivalent) (Wang et al. 2003), we used the same doses of alcohol in the high-dose alcohol (HDA) group (Japanese Sake, containing 15% ethanol: 4.5 ml ⁄ kg ⁄ day in 100% ethanol equivalent), although the administration period was only 4 weeks in our study. Secondly, they comment about the short period of alcohol administration used. A previous study reported that bone marrow fat cell enlargement was observed in the subchondral area of the femoral head in rabbits treated with alcohol for 2 months or longer (Wang et al. 2003). In contrast, one of the purposes of the present study was to observe the histological changes in the early phase (within 4–6 weeks), which has been reported to be a sufficient period to observe steroid-induced ON. Thirdly, they comment about the buffer period of about 2 weeks without treatment before the tissue sample collection. In steroid-induced ON, the ON is apparent experimentally within 2 weeks of steroid administration, because repair tissue for ON is observed in 2 weeks (Miyanishi et al. 2002; Motomura et al. 2004). However, no data has been shown regarding the timing when ON occurs after alcohol administration. In addition, we do not know whether the repair process for ON is impaired following the alcohol administration or not. Therefore, we adopted the 2-week observation period without alcohol administration to determine when ON occurs based on the degree of repair tissue. The differences in the doses, administration periods and the observation periods, may influence the occurrence of alcohol-related ON. We agree completely that further studies should be performed based upon the findings obtained in previous reports and carefully taking differences in protocol into consideration in interpreting the outcomes.