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Rheumatology 2001; 40: 196-201
© 2001 British Society for Rheumatology

A high low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio as a potential risk factor for corticosteroid-induced osteonecrosis in rabbits

K. Miyanishi, T. Yamamoto, T. Irisa, A. Yamashita, S. Jingushi, Y. Noguchi and Y. Iwamoto

Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objective. This study was designed to determine the potential risk factors for corticosteroid-induced osteonecrosis (ON) based on lipid metabolism, using a rabbit ON model.

Methods. Blood samples were obtained from 38 rabbits, which then received a single intramuscular injection of 20 mg/kg methylprednisolone acetate. Four weeks after the injection, the femora and humeri were examined histopathologically for the presence of ON, and the sizes of the bone marrow fat cells were also measured.

Results. Rabbits with and without ON differed significantly in the ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol (LDL/HDL cholesterol ratio), which is considered to be a serological marker of lipid transport (P=0.026). The marrow fat cells were significantly larger in the rabbits with ON than in those without ON (P<0.0001).

Conclusion. A higher LDL/HDL cholesterol ratio was significantly associated with the development of ON, and such an elevated ratio may partly contribute to the increased size of marrow fat cells.

KEY WORDS: Osteonecrosis, Corticosteroid, LDL/HDL cholesterol ratio, Rabbit, Lipid transport, Bone, Femoral head, Risk factor.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Non-traumatic osteonecrosis (ON) of the femoral head is a devastating disease, and generally occurs in the third to fifth decades of life [1, 2]. Total hip replacement has been one of the major therapeutic options [2]; however, a higher rate of early failure has been reported in younger ON patients [3, 4]. Prevention is thus the ideal strategy, and therefore the possible risk factors have been investigated in order to identify patients susceptible to ON.

ON is known to occur in patients who have received corticosteroids for the treatment of underlying diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis and leukaemia [1, 2, 5]. It would therefore be ideal if we could assess the risk of ON prior to corticosteroid treatment. Recently, a high level of lipid transport has been reported in human ON cases [6]. Increased size of bone marrow fat cells has also been reported to be associated with corticosteroid-induced ON [7].

This study was designed to determine the potential risk factors for corticosteroid-induced ON in rabbits, based on lipid metabolism.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
The rabbit model of corticosteroid-induced ON that we used in this study has been described in a previous paper [8].

Animals
Adult (growth plate closed) male Japanese white rabbits (Kyudo, Tosu, Japan), weighing 3.2–3.8 kg, were used at the Animal Centre of Kyushu University and were maintained on a standard laboratory diet and water. The ages of the rabbits ranged from 28 to 31 weeks. All experiments were reviewed by the Common Ethics Committee for Animal Experiments at Kyushu University, and were conducted in accordance with the Guidelines for Animal Experiments of Kyushu University, Japanese law (no. 105), and the notification (no. 6) of the government and the Committee on Ethics in Japan.

Haematological examination
Blood samples were obtained from all rabbits in a fasting state between 7 and 9 a.m. Haematological and chemical evaluations were made for 15 serological factors, including the white blood cell count, red blood cell count, haemoglobin, haematocrit, platelets, total cholesterol, triglycerides, very low-density lipoprotein (VLDL), chylomicron, ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol (LDL/HDL cholesterol ratio), free fatty acids (FFA), glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, C-reactive protein (CRP) and fibrinogen.

The total cholesterol, triglyceride, low-density lipoprotein cholesterol and FFA levels were measured by enzymatic methods [9–12]. High-density lipoprotein cholesterol was measured with polyethylene glycol-modified enzymes and sulphated {alpha}-cyclodextrin [13]. VLDL and chylomicron were measured by the turbidimetric method [14]. Fibrinogen was measured using a thrombin reagent kit (Dade Behring, Newark, DE, USA). CRP was measured by a turbidimetric immunoassay [15].

Treatment
After blood samples had been obtained from all rabbits, 38 rabbits were injected once with 20 mg/kg body weight methylprednisolone acetate (MPSL) (Upjohn, Tokyo, Japan) into the right gluteus medius muscle. All rabbits were killed 4 weeks after the injection of MPSL. The animals were anaesthetized with an intravenous injection of pentobarbital sodium (25 mg/kg body weight) (Abbott, Chicago, IL, USA), and were then killed by aortectomy.

Tissue preparation
For light microscopic examinations, both femora and both humeri (a total of four bone samples) were obtained at the time of death, and were fixed for 1 week with 10% formalin–0.1 M phosphate buffer, pH 7.4. The bone samples were decalcified with 25% formic acid for 3 days and were then neutralized with 0.35 M sodium sulphate for 3 days. The bone samples from the femora and humeri were cut along the coronal plane in the proximal one-third and the axial plane in the distal part (condyle). The specimens were embedded in paraffin, cut into 4 µm sections, and stained with haematoxylin and eosin.

Evaluation of ON
The whole area of the proximal one-third of both femora and humeri and whole sections of the condyles of both femora and humeri, a total of eight regions, were examined histopathologically for the presence of ON. ON was assessed blindly by three authors (KM, TY, TI) without knowledge of the haematological results. The diagnosis of ON was based on the diffuse presence of empty lacunae or pycnotic nuclei of osteocytes in the bone trabeculae, accompanied by surrounding bone marrow cell necrosis [8, 16]. All rabbits that had at least one osteonecrotic lesion out of eight areas examined were considered to be osteonecrotic (ON+) while those with no osteonecrotic lesions were considered to be non-osteonecrotic (ON-).

Measurement of intraosseous lipid deposition
As described in a previous report [7], intraosseous lipid deposition was quantitatively determined by measuring the size of the bone marrow fat cells using a Power Macintosh computer and NIH image software [17]. The fat-cell size was calculated as the average of the greatest diameters of 25 fat cells in four randomly selected locations in the proximal one-third of the right femur. Briefly, an image of the sections was obtained with a camera and was directed electronically to the image processor, where it was digitized, and then analysed by computer. The projected image of the fat cells displayed on the video monitor was measured using an interactive mousepad tracing instrument, while the corresponding morphometric data were processed automatically by the computer system. Fat cells that had undergone necrosis were excluded from the evaluation of fat-cell size. The metaphyseal and/or diaphyseal regions were examined because ON has been seen in these areas in this rabbit model [8].

The repeatability of the measurement method of marrow fat-cell size was determined by having two authors (KM and TY) measure each value of the 38 rabbits on two occasions at a 1-week interval [18]. The interobserver differences (the differences between the measurements by KM and the other measurements by TY for the values in each rabbit) were the mean values of the differences in all rabbits. The intraobserver differences (the differences between two measurements at different times by KM for the same rabbit) were the mean values of the differences in all rabbits. The interobserver and intraobserver coefficients of repeatability were also calculated.

Statistical analysis
The data on the haematological examinations and fat-cell sizes are given as the mean±S.D. All haematological data and fat-cell sizes were compared between the ON+ and ON- rabbits, using Student's t-test. For correlations between the LDL/HDL cholesterol ratio and the number of osteonecrotic lesions, we used the Spearman correlation coefficient. P<0.05 was considered to be significant. All analyses were performed using SPSS 6.1J on a Macintosh computer (SPSS Japan, Tokyo, Japan).


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Prevalence and location of ON
The incidence of ON+ rabbits was 29/38 (76%). ON was located in the metaphysis and/or the diaphysis, but not in the epiphysis.

Histopathological features
Macroscopically, ON in both the femur and humerus was observed in the metaphysis and/or the diaphysis as yellowish-coloured areas. Histologically, ON lesions showed an accumulation of bone marrow cell debris and bone trabeculae demonstrating empty lacunae (Fig. 1AGo). The accumulation of serofibrinous exudate as part of a repair process was also seen around the necrotic area. Both the femur and the humerus of a corticosteroid-treated rabbit that did not develop ON consisted of normal bone trabeculae and normal bone marrow cells (Fig. 1BGo). An intraosseous vein occluded by fat emboli was noted in the metaphysis of the femur in three rabbits with ON (Fig. 1CGo).



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  		FIG. 1. (A) Histological features of osteonecrosis in a corticosteroid-treated rabbit. The bone trabeculae show empty lacunae, while the surrounding marrow tissue consists of necrotic marrow cell debris. Haematoxylin/eosin staining, 200x magnification. (B) Photomicrograph of a femur of a corticosteroid-treated rabbit that did not develop osteonecrosis, which consists of normal bone trabeculae and normal bone marrow cells. Haematoxylin/eosin staining, 200x magnification. (C) The intraosseous vein is occluded by a fat embolus in the metaphysis of the proximal femur of a rabbit with osteonecrosis (arrow). Haematoxylin/eosin staining, 200x magnification.

 

Haematological examination
A significant difference was observed in the LDL/HDL cholesterol ratio between the ON+ (0.44±0.10) and ON- (0.34±0.14) rabbits (P=0.026). The remaining 14 serological factors, including cholesterol and triglyceride, showed no significant difference between the two groups (Table 1Go).


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  		TABLE 1. Results of the haematological examinationa

 
Correlation between the LDL/HDL cholesterol ratio and the number of osteonecrotic lesions
Multifocal ON lesions were identified in both the femur and humerus. The ON+ rabbits were found to have a mean of 2.4 sites (range 1–6) with ON. Ten rabbits showed one involved lesion, while 11 rabbits had two lesions, one rabbit had three lesions, three rabbits had four lesions, and four rabbits had six lesions. No rabbits had five, seven or eight ON lesions. A significant correlation was found between the LDL/HDL cholesterol ratio and the number of osteonecrotic lesions (Fig. 2Go; {rho}=0.583, P=0.0004).



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  		FIG. 2. A significant correlation was found between the LDL/HDL cholesterol ratio and the number of osteonecrotic lesions ({rho}=0.583, P=0.0004). The LDL/HDL cholesterol ratios of the rabbits without osteonecrosis are plotted at 0 on the abscissa.

 

Measurement of intraosseous lipid deposition
The size of the marrow fat cells increased significantly more in the ON+ rabbits (diameter 58.8±6.7 µm) than in the ON- rabbits (diameter 46.8±3.5 µm) (P<0.0001).

The mean interobserver and intraobserver differences of the measured variables were 0.09 µm (range -1.90 to 2.78; 95% confidence interval -0.33 to 0.51) and 0.06 µm (range -1.79 to 3.21; 95% confidence interval -0.31 to 0.43) respectively. The interobserver and intraobserver coefficients of repeatability were 2.57 and 2.26 µm respectively.


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
Both hypercoagulability and hypofibrinolysis have been reported in human non-traumatic ON cases, including a high plasminogen activator inhibitor [19], high lipoprotein (a) [19], and the presence of anticardiolipin antibodies [20]. These risk factors are useful when considering the pathophysiology of ON. However, the causality between these abnormalities and the development of ON or corticosteroid administration has not yet been fully clarified, because they were identified in patients who had either already developed ON or received corticosteroid treatment. Since the same dose of corticosteroids does not cause ON equally in every patient [5], there may be individual variations in susceptibility to the development of ON before starting corticosteroid administration. In this study, the serological factors were thus examined prior to the steroid administration, and correlated with the occurrence of ON 4 weeks after steroid administration. Assessment of the serological factors after steroid administration may be less important in order to determine a potential risk factor. Such a study design, in which the relationship between risk factors in a cross-sectional survey and the subsequent occurrence of a disease is investigated, has also been employed in other studies [21–23]. In the Bogalusa Heart Study, baseline serum lipoprotein levels in cross-sectional surveys were correlated with coronary artery fatty streaks at autopsy [21].

Ideally, blood samples should be collected from patients with collagen diseases before steroid treatment. Patients with SLE have been often used to investigate the pathogenesis of ON because they show a high frequency of ON [5]. The average incidence rate of SLE was reported to be 5.56 per 100 000 in the USA [24]. In order to detect the occurrence of ON, SLE patients receiving steroid treatment should be observed using magnetic resonance imaging for at least 6 months [25]. Considering both this relatively low incidence rate of SLE and the long follow-up period, we estimate that it would take more than 2 yr to collect data on a sufficiently large number of newly diagnosed cases of SLE to reach statistical significance. Compared with such a clinical prospective study in man, an animal study is easier to conduct. Many rabbits can be used simultaneously and ON can be determined histologically 4 weeks after steroid administration. In addition, rabbits have been reported to be a good model for human pharmacokinetic studies of corticosteroids [26]. The rabbit ON model was thus used to assess the potential risk factors for ON in this study.

A high LDL/HDL cholesterol ratio is considered to reflect prominent lipid transport to the peripheral tissue [27–29]. Such lipid transport has been suggested to be a risk factor for human ON [6]. We thus consider that a high LDL/HDL cholesterol ratio may be predictive of human ON. Rabbit ON shows other similarities to human ON. First, the multifocal nature of the ON is similar to that in humans [1, 8, 30]. Secondly, the histopathology of ON in this model is characterized by empty lacunae accompanied by surrounding bone marrow cell necrosis and the resulting reparative changes, which are analogous to those in humans [8, 31]. These similarities suggest significant relevance of this animal model to human ON.

It should be noted that a high LDL/HDL cholesterol ratio does not necessarily correspond to a high serum level of cholesterol, since the serum cholesterol level reflects the total delivery to and from the peripheral tissues. In this study, no significant difference was seen in the levels of cholesterol and triglyceride between the ON+ and ON- rabbits. However, significant lipid transport resulting from a high LDL/HDL cholesterol ratio may have led to at least a local (intraosseous) hyperlipidaemic state in the ON+ rabbits. This view is supported by the increased fat-cell size of ON+ rabbits in this study, as well as other clinical and experimental studies of ON [32, 33]. Boskey et al. [32] specifically reported significant cholesterol deposition in surgically removed human osteonecrotic femoral heads. Kawai et al. [33] reported the relationship between a decrease in HDL associated with lipid deposition in bone tissue and the development of ON in heritable hyperlipaemic rabbits.

Regarding the pathogenesis of corticosteroid-induced ON, the concept of increased bone marrow pressure has been proposed, in which initial ischaemia is produced by intraosseous circulatory disturbances which result from thrombi, fat emboli and/or increased marrow fat-cell size [7, 34]. In this study, both the LDL/HDL cholesterol ratio and fat-cell size were significantly higher in the ON+ rabbits than in the ON- rabbits. Fat emboli were identified in three ON+ rabbits, while no fat emboli were found in ON- rabbits. Based on these data, a higher LDL/HDL cholesterol ratio may partly enhance this corticosteroid-induced circulatory obstruction, and thereby contribute to the development of ON (Fig. 3Go).



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  		FIG. 3. Postulated pathogenesis of corticosteroid-induced ON. Initial ischaemia is produced by an intraosseous circulatory obstruction with fat emboli and/ or increased bone marrow fat-cell size, which subsequently leads to the development of ON. A higher LDL/HDL cholesterol ratio may partly enhance this corticosteroid-induced circulatory obstruction.

 
Although we have focused on lipid metabolism in this study, hypercoagulability and hypofibrinolysis have also been reported to play a causative role in human ON [19, 20]. It is postulated that these factors enhance the coagulability which leads to thrombosis. Corticosteroids are known to induce not only hyperlipidaemia but also a hypercoagulable and hypofibrinolytic state of plasma [35, 36]. The pathogenesis of corticosteroid-induced ON is considered to be multifactorial, and it seems clear that no one factor adequately accounts for the development of ON [2]. It is therefore not surprising that both hyperlipidaemia (general or local) and coagulopathy may be closely associated with the development of corticosteroid-induced ON.

Such a multifactorial nature of ON may partly explain why the LDL/HDL cholesterol ratio did not show a much better (lower) P-value. A high LDL/HDL cholesterol ratio is considered to be a reasonable risk factor to understand the pathogenesis of ON. We thus consider that an association between the development of ON and a high LDL/HDL cholesterol ratio is essentially valid in spite of this relatively high P-value.

There have been a few reports regarding the factors that contribute to the multiple-site development of ON [37, 38]. LaPorte et al. [37] reported the relationship between multifocal osteonecrosis and corticosteroid therapy. Egan and Munn [38] demonstrated an association between the antiphospholipid antibody syndrome and multiple sites of ON. These studies offer additional evidence that systemic abnormalities may be associated with multifocal ON. A current animal study suggests that the systemic nature of prominent intraosseous lipid transport resulting from a higher LDL/HDL cholesterol ratio may contribute to the development of multifocal ON, as well as the development of ON itself.

In this study, all rabbits used were as similar as possible regarding gender, weight, diet and age. We thus consider that the rabbits were almost homogeneous in nature, and therefore the significant difference in the LDL/HDL cholesterol ratio is not considered to have been influenced by these confounding factors.

In conclusion, a high LDL/HDL cholesterol ratio was found to be significantly associated with the development of ON as a potential risk in corticosteroid-treated rabbits. The concept of intraosseous lipid transport may be useful not only for assessing the potential risk of ON, but also for exploring its possible mechanism in the future.


   Notes
 
Correspondence to: K. Miyanishi, Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan Back


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Submitted 23 February 2000; Accepted 11 September 2000


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