Drug for preventing or treating steroid-induced osteonecrosis of femoral head, and use thereof

Abstract

A drug for preventing or treating steroid-induced osteonecrosis of the femoral head, comprising an active ingredient cycloastragenol. The drug can remarkably improve intraosseous blood supply in the steroid-induced osteonecrosis of the femoral head, reduce formation of necrotic areas and empty lacunae, decrease excessive bone resorption and reduce CTSK protein expression, and provide a potential prevention and treatment scheme for treatment of steroid-induced osteonecrosis of the femoral head.

Description

A drug for preventing or treating steroid-induced osteonecrosis of the femoral head and its application Technical Field The present invention belongs to the field of biomedical technology, and specifically relates to a drug for preventing or treating steroid-induced osteonecrosis of the femoral head, and also relates to the application of the drug in the preparation of a drug for preventing or treating steroid-induced osteonecrosis of the femoral head. Background Art Osteonecrosis of the femoral head (ONFH) is an orthopedic disease that seriously endangers people's health. Patients present with hip joint pain and limited mobility. In the past, in the advanced stage, the femoral head could collapse and be complicated with hip arthritis, resulting in the need for hip joint replacement in patients. Currently, there are 10 million patients with osteonecrosis of the femoral head in China, and the main population of onset is young and middle-aged people, bringing a heavy burden to individuals and society. Trauma, alcohol use, and steroid use are the main inducements for osteonecrosis of the femoral head. Among them, steroids are an important inducement for osteonecrosis of the femoral head in China. During the COVID-2019 pandemic, the use of steroids has increased significantly, increasing the risk of steroid-induced osteonecrosis of the femoral head. Currently, there is still a lack of effective preventive and therapeutic drugs for steroid-induced osteonecrosis of the femoral head. Patients need to undergo surgical treatments such as core decompression and iliac bone grafting. In addition to the risks of the surgery itself, patients also need to face problems such as a long postoperative rehabilitation period, which is undoubtedly a heavy burden. In the advanced stage, joint replacement is required, and this surgery will face risks such as prosthesis revision, prosthesis loosening, and even catastrophic periprosthetic infection. Traditional Chinese medicine has been used for a long time in the treatment of orthopedic diseases. Deeply exploring the active ingredients will provide potential compounds for the development of new preventive and therapeutic drugs. The present invention provides a drug for preventing or treating steroid-induced osteonecrosis of the femoral head, which can prevent and treat steroid-induced osteonecrosis of the femoral head, is expected to delay the progression of the disease, postpone hip joint replacement in patients, and improve the quality of life. Summary of the Invention The present invention provides a drug for preventing or treating steroid-induced osteonecrosis of the femoral head, which solves the deficiency in the prior art that the treatment of steroid-induced osteonecrosis of the femoral head mostly uses surgical treatments and lacks exact drug treatment means. To achieve the above object, the present invention adopts the following technical solutions: A drug for preventing or treating steroid-induced osteonecrosis of the femoral head, comprising the active ingredient cyclocophorol. Further, the drug for preventing or treating steroid-induced osteonecrosis of the femoral head is an inhibitor of CTSK protein expression in the femoral head. A pharmaceutical composition, comprising an effective dose of the above-mentioned drug for preventing or treating steroid-induced osteonecrosis of the femoral head and a pharmaceutically acceptable carrier. Further, the carrier includes one or more of a buffering agent, an emulsifying agent, a suspending agent, a stabilizing agent, a preservative, an excipient, a filler, a coagulant and a blending agent, a surfactant, a dispersant or an antifoaming agent. In the present invention, the drug further includes a pharmaceutically acceptable diluent. Further, the diluent is one of distilled water, physiological sodium chloride or phosphate buffered saline, and glucose solution. Further, the administration method of the pharmaceutical composition is gastrointestinal administration or parenteral administration. In the present invention, the dosage form of the pharmaceutical composition is one of tablets, capsules, granules, pills, oral liquids or injections. Further, the dosage of the drug for preventing or treating steroid-induced osteonecrosis of the femoral head is 5 mg / kg - 15 mg / kg. Use of a drug for preventing or treating steroid-induced osteonecrosis of the femoral head in the preparation of a drug for preventing or treating steroid-induced osteonecrosis of the femoral head. Further, the steroid-induced osteonecrosis of the femoral head is osteonecrosis of the femoral head caused by the application of supra-physiological doses of glucocorticoids. The present invention has the following beneficial effects: The drug for preventing or treating steroid-induced osteonecrosis of the femoral head in the present invention can significantly improve the blood supply in the femoral head of steroid-induced osteonecrosis of the femoral head, reduce the formation of necrosis areas and empty bone lacunae, reduce excessive bone resorption and reduce the expression of CTSK protein, providing a potential prevention and treatment plan for the treatment of steroid-induced osteonecrosis of the femoral head. Description of the Drawings The technical solution of the present invention will be further described below in conjunction with the specification drawings and specific embodiments. Figure 1 is a flow chart of the experiment on cyclocophorol intervention in steroid-induced osteonecrosis of the femoral head in rats; Figure 2 shows the changes in the body weight of rats during the experiment; Figure 3 shows the angiography of the femoral head in different treatment groups; Figure 4 shows the Micro-CT scan of the femoral head of rats in different treatment groups; Figure 5 shows the frontal two-dimensional image of the femoral head of rats scanned by Micro-CT in different treatment groups and the two-dimensional and three-dimensional images of ROI1 and ROI2; Figure 6 shows the bone parameters of ROI1 in the femoral head of rats in different treatment groups; Figure 7 shows the bone parameters of ROI2 in the femoral head of rats in different treatment groups; Figure 8 shows the expression of the bone resorption protein CTSK in the bone tissue of rats with steroid-induced osteonecrosis of the femoral head improved by cyclocophorol; Figure 9 shows the HE staining images of the femoral head tissue sections of rats in different treatment groups; Figure 10 shows the statistical results of empty lacuna rate in different treatment groups. Detailed implementation mode As one of the main components of Astragalus membranaceus, cyclocumarin, a triterpenoid saponin compound, has been reported to have anti-aging and antioxidant effects. The inventors found that cyclocumarin can inhibit RANKL-induced osteoclast formation and bone resorption function, and can improve bone loss in osteoporotic mice. However, there is no report on its prevention and treatment of steroid-induced osteonecrosis of the femoral head. In this invention, animal experiments were conducted to clarify that cyclocumarin can inhibit methylprednisolone-induced osteonecrosis of the femoral head in rats, and its mechanism of action is related to the inhibition of osteoclasts. As shown in Figure 1, the experimental flow chart of cyclocumarin intervention in rats. Note: Gluteus injection: Gluteal muscle injection; Intraperitoneal injection: Intraperitoneal injection. Nine-week-old female SD rats were randomly divided into a solvent control group (Control), a model group (MPS), a low-dose cyclocumarin intervention group (MPS + CAG (5 mg / kg)), and a high-dose cyclocumarin intervention group (MPS + CAG (15 mg / kg)), with 6 rats in each group. Each group was marked with a different color, and each point represents a rat. Modeling method: Methylprednisolone was injected into the gluteal muscle (20 mg / kg) on the 1st - 3rd day of each week for three consecutive weeks, a total of 9 times. Then, the intervention was stopped for 3 weeks. At the 6th week after the first modeling, 3 rats were randomly selected from each group for barium sulfate cardiac perfusion angiography. After that, all rats were sacrificed and dissected, and Micro-CT scans were performed to obtain the blood vessel conditions and bone structures of the femoral heads. Western Blot was used to detect the protein expression in bone tissues. The specific process is as follows: 1. Acquisition and grouping of SPF-grade experimental SD rats Twenty-four 9-week-old SPF-grade female SD rats were purchased from the Experimental Animal Center of Guangzhou University of Chinese Medicine (Sanyuanli, SCXK[Guangdong]2013 - 0034), and the SPF animal certificate number is 44005800008479. The experimental design and experimental ethics of this study were approved by the Animal Experiment Ethics Committee of Guangzhou University of Chinese Medicine (Ethics number: 20190722001). After all rats were purchased, they were weighed and numbered in ascending order. Using EXCEL to establish a function, they were randomly divided into a solvent control group (body weight 222.4 ± 15.84 g), a GIONFH model group (body weight 222.9 ± 13.28 g), a low-dose cyclocumarin intervention group (dose 5 mg / kg) (body weight 223.6 ± 14.46 g), and a high-dose cyclocumarin intervention group (dose 15 mg / kg) (body weight 224.1 ± 12.81 g), with 6 rats in each group. After grouping, each group was placed in a standard cage and fed adaptively for 1 week before modeling. All rats were fed with ordinary feed, allowed to eat and drink freely, and kept under 24-hour cyclic light. The animals were checked regularly every day. 2. Rat model of GIONFH and intervention with cyclocophorol After 1 week of adaptive feeding, all rats were weighed again. The dosages of methylprednisolone (20 mg / kg) by intramuscular injection and different dosages of cyclocophorol (5 mg / kg and 15 mg / kg) by intraperitoneal injection were calculated according to the body weight. Methylprednisolone and cyclocophorol were dissolved with sterile saline (0.5% DMSO) as the solvent. During model establishment, methylprednisolone was injected into the gluteal muscle of the model group, and attention was paid to alternating between the two gluteal muscles. In the different-dose cyclocophorol intervention groups, after intramuscular injection of methylprednisolone, cyclocophorol solution was injected intraperitoneally, while the solvent control group was given an equal volume of sterile saline (0.5% DMSO) by intraperitoneal injection. The model establishment was carried out on the 1st - 3rd day of each week for 3 consecutive times, with an interval of 24 h each time, for 3 consecutive weeks, with a total of 9 interventions. During this period, a new syringe was used for each injection, and no antibiotics were used, and then the intervention was stopped for 3 weeks. During the experiment, the status of the rats was observed every day, and records were made and processed in a timely manner. The body weight changes of the rats were recorded once a week, and the drug dosage was adjusted accordingly. At the 6th week after the first model establishment, 3 rats with the lowest, middle, and highest body weights were selected from each group (6 rats in the high-dose cyclocophorol intervention group, and 1 rat was randomly selected from the two rats ranked 3rd and 4th in body weight ranking through an EXCEL function). After anesthetizing the above 3 rats in each group, barium sulfate cardiac perfusion angiography was performed, and the other rats were sacrificed after overdose anesthesia. Then, bone tissue samples were taken from all rats. The bilateral femurs were stored in 4% PFA, and the bilateral tibias were washed with ultrapure water and then stored in a -80°C refrigerator. As shown in Figure 2, there were no significant differences in the baseline body weight levels (at the 0th and 1st weeks) of the rats in each group, as shown in Figure 2A and Figure 2B. The changes in the body weight of the rats during the entire cyclocophorol intervention process (once a week) are shown in Figure 2C. 3. Barium sulfate suspension cardiac perfusion angiography The dosage of anesthesia was calculated according to the body weight of the rats at the end of the 6th week after model establishment. Before anesthesia, a barium sulfate suspension with a mass-volume concentration of 30% (15 g barium sulfate∶50 ml gel) was prepared in advance. The specific method was to first inject the sterilized gel into a 50 ml centrifuge tube and heat it in a 40°C water bath until it completely melted into a water-like state. Gradually add sub-nanometer barium sulfate (diameter < 0.8 μm) in small amounts multiple times, and continuously shake during this period to promote the continuous fusion of the two. Finally, a barium sulfate suspension like thick milk was formed, and it was continuously heated and shaken at 40°C for standby. After the anesthesia takes effect, the rat is fixed in the beach position on a rack modified from a mouse cage cover. The bilateral forelimbs are fixed with a long tail clip. The surgical scissors make a longitudinal incision upward from the junction of the chest and abdomen in the midline of the abdomen, gradually exposing the thoracic diaphragm, and the diaphragm is completely cut from the middle to both sides along the inner wall of the thorax. During this period, the rat has pneumothorax and shakes. When the rat calms down, the surgical scissors cut the ribs upward along both sides of the sternum (because there are accompanying thoracic arteries and veins close to both sides of the sternum, which may affect the perfusion effect after injury) until the root of the heart and lungs are completely exposed. Flip the sternum backward and fix it to keep the heart surgical field clear. Use tissue forceps to open the thymus and see the white translucent aortic arch above the heart. At this time, the operator holds the heart with the thumb and index finger of one hand, and holds a homemade perfusion needle with a diameter of 1.2mm (the tip of a 20ml syringe needle is smoothed and the tail is tied with silk thread) in the other hand. Pierce the heart from the apex, and continue to slide slowly toward the aortic arch after feeling the sense of emptiness until the needle tip is seen through the aortic root. Fix the perfusion needle to the chest with the silk thread at the tail to prevent it from slipping out during the operation. After completing the fixation of the perfusion needle, the operator carefully lifts the right atrial appendage with micro forceps and cuts it with micro scissors to allow venous blood to flow out. Then hold a 50ml syringe and continue to slowly perfuse the heart with 50IU / ml heparin sodium (25000IU: 500ml saline) until the mesentery becomes completely transparent and clear heparin sodium solution flows out of the right atrial appendage (about 150ml / mouse). After heparinization, the operator wears a protective mask, replaces the syringe and slowly perfuses the heart with 4% PFA, and maintains the perfusion until the right atrial appendage flows out of clear PFA (about 50 ml / rat). After PFA fixation, replace a new 50 ml syringe to extract the barium sulfate solution, maintain a certain pressure and slowly push it at a uniform speed. It can be seen that the mesenteric microvessels are gradually filled with barium sulfate. Continue to perfuse until it can no longer be pushed. Finally, it is best if the right atrial appendage can flow out of the barium sulfate solution. After the rat is cleaned with ultrapure water, it is transferred to a 4° refrigerator overnight. The next day, the femurs on both sides are sampled and fixed in 4% PFA at room temperature. As shown in Figure 3, the red color indicates that the blood vessels are filled with contrast agent. Among them, angiography showed that the blood supply in the femoral head was abundant in the solvent control group, and the blood supply in the femoral head was reduced in the model group. The intervention of cycloastragenol improved the blood supply of the femoral head in a dose-dependent manner. Femoral head angiography proved that cycloastragenol improved the reduced blood supply in the femoral head of rats with steroid-induced femoral head necrosis. 4. Bone parameter analysis and vascular image extraction after Micro-CT scanning reconstruction After the rat bone tissue was fixed for 48 h, the part from above the lesser trochanter to the femoral head was scanned by Micro-CT. The scanning parameters were as follows: 80 kV, 100 μA, 0.5 mm Al filter, 1K resolution, 0.6° rotation step, and 12 μm pixel. After the scanning was completed, three-dimensional reconstruction was performed using NRecon. The reconstruction parameters were as follows: ring artifact correction = 7, smoothing = 1, beam hardening correction = 33%, and the image conversion threshold was uniformly set to 0 - 0.0771. The three-dimensional image after the reconstruction was loaded into CTvox. After confirming that the femoral head was completely scanned, it was imported into Dataviewer. The postures of each cross-section of the femoral head were manually adjusted to make the line passing through the vertex of the femoral head and the center of the epiphysis approximately perpendicular to the horizontal plane in the virtual space. All samples were processed in this way, so that the ROIs between the samples tended to be consistent. After the adjustment, two-dimensional images of three cross-sections of the femoral head were exported respectively. The two-dimensional image of the horizontal plane was imported into the CTan software, and two ROIs were selected above and below the epiphyseal line respectively.

[0132] Specifically, first, the highest point of the center of the growth plate was determined as the reference. From this, upward and downward offsets of 0.203 / 0.799 mm (about 1 mm in total for up and down) were set respectively. Cylindrical regions with a height of 0.3 mm and a radius of 0.65 mm above the upper region and below the lower region were selected as ROI1 and ROI2 respectively. The binarized gray threshold was set to 100 - 255, and the bone parameters of the corresponding ROIs were obtained using the three-dimensional analysis function, including bone volume fraction (BV / TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), and trabecular separation (Tb.Sp). For the femoral head with barium sulfate angiography, the three-dimensional image after the above scanning and reconstruction was imported into CTvox, and the curve in the channel was manually adjusted to separate the blood vessels filled with barium sulfate from the femoral head. As shown in Figure 4, the trabecular structure of the femoral head in the solvent control group was normal, and necrosis cavities were formed in the femoral head of the model group (the white arrow in the femoral head indicates the necrotic area). Cycloastragenol improved the formation of necrosis cavities in the femoral head in a dose-dependent manner. Micro-CT reconstruction demonstrated that cycloastragenol improved the formation of the necrotic area in rats with steroid-induced osteonecrosis of the femoral head. As shown in Figure 5, the frontal plane two-dimensional images of the femoral head of rats, and the two-dimensional and three-dimensional images of ROI1 and ROI2, and Figures 6 and 7 are the bone parameters of ROI1 and ROI2 of the femoral head of rats. Note: COR: frontal plane; TRA: horizontal plane; ROI1: region of interest above the epiphyseal line; ROI2: region of interest below the epiphyseal line; BV / TV: bone volume fraction; Tb.N: trabecular bone number; Tb.Th: trabecular bone thickness; Tb.Sp: trabecular bone separation. * in the statistical chart represents P < 0.05. The results showed that the trabecular bone in different regions of the femoral head in the solvent control group was rich, the bone resorption in the femoral head in the model group increased significantly, and astragaloside IV improved the bone resorption in the femoral head in a dose-dependent manner. 5. Protein immunoblotting experiment of rat bone tissue Take out the bilateral bone tissues of the rats without angiography from the -80 °C refrigerator, immediately put them into a mortar filled with liquid nitrogen and grind them by hand. Keep adding liquid nitrogen during the process to maintain a low temperature state. After sufficient grinding, weigh an equal amount of bone powder for each group, add RIPA protein lysate (containing 10 μl PMSF) according to 100 mg∶1 ml, shake well and lysate on ice for 30 min, transfer to a centrifuge at 4 °C, centrifuge at 12000 r / min for 20 min, carefully aspirate the protein supernatant with a pipette, add 1 / 4 volume of 5×SDS-PAGE protein loading buffer, boil at 100 °C in a water bath for 5 min to fully denature the protein, and then promptly aliquot and store at -20 °C in the refrigerator for later use. Boil the protein sample again and centrifuge before electrophoresis. Prepare 10% and 12% gels (1.5 mm, 15 wells) according to the instructions, and pre-dilute the primary antibody and secondary antibody with 1% skim milk (1×TBST). The protein loading amount is 15 μl, perform electrophoresis at room temperature (110 kV, 90 min), transfer the membrane on ice (200 mA, 2 h), block with 5% milk (room temperature, 1 h), incubate with the primary antibody (4 °C, overnight), wash the membrane (room temperature, 3×5 min), incubate with the secondary antibody (room temperature, 2 h), wash the membrane (room temperature, 3×5 min), soak the membrane in ECL developing solution and then place the membrane in an imaging system, set automatic exposure, and quantitatively analyze the gray scale of the exported image with Image J. For proteins with close positions, after adding membrane regeneration solution to elute, detect other proteins according to the above method. As shown in the representative WB image in Figure 8 (Figure 8A), and the expression of CTSK protein (Figure 8B), * in the statistical chart represents P < 0.05. The expression of CTSK in the femoral head in the solvent control group was low, the expression of CTSK in the femoral head in the model group increased significantly, and astragaloside IV improved the expression of CTSK in a dose-dependent manner. It was proved that astragaloside IV improved the expression of bone resorption proteins in the bone tissue of rats with steroid-induced osteonecrosis of the femoral head. 6. HE staining experiment of rat femoral head tissue sections After Micro-CT scanning, the same number of rat femoral heads (n = 3) were selected from each group for pathological observation. First, the femoral heads were soaked in 14% ethylenediaminetetraacetic acid (EDTA) (NeoFroxx, Germany) at room temperature for 2 weeks for decalcification, and the solution was changed daily. Then, conventional dehydration with ethanol and paraffin embedding were performed. Tissue sections with a thickness of 5 μm were prepared using an RM 2155 Biocut Microtome (Leica, Germany), loaded onto glass slides, and stained with HE. Panoramic scanning of the sections was completed using a Pannoramic MIDI slide scanner (3DHistech, Hungary), and quantitative analysis of the (empty) bone lacunae in the femoral head was performed using the SlideViewer software (3DHistech, Hungary) supplied with the scanner. As shown in Figure 9, the HE staining image of the rat femoral head tissue section and the statistical situation of the empty bone lacuna rate are shown in Figure 10. Note: CAG, cyclocophorol; MPS, methylprednisolone; HE, hematoxylin and eosin staining; GIONFH, glucocorticoid-induced osteonecrosis of the femoral head. The appearance of * in the statistical chart represents P < 0.05. The results showed that there were fewer empty bone lacunae in the femoral head of the solvent control group, the number of empty bone lacunae in the femoral head of the model group increased, and cyclocophorol intervention dose-dependently reduced the formation of empty bone lacunae. The empty bone lacunae (necrotic-like area) and bone lacunae (normal area) above the epiphysis were marked with black arrows and green arrows respectively, and the empty bone lacuna rate was the ratio of the number of empty bone lacunae to the total number of (empty) bone lacunae. Example 1 A drug for preventing or treating osteonecrosis of the femoral head caused by hormones, comprising the active ingredient cyclocophorol. In this example, cyclocophorol can improve the reduced blood supply of the femoral head in rats with osteonecrosis of the femoral head caused by hormones, reduce the formation of necrotic areas and empty bone lacunae, and reduce excessive bone resorption; and reduce the expression of CTSK protein, and can be used as an inhibitor of CTSK protein expression in the femoral head. Example 2 A pharmaceutical composition, comprising an effective dose of the above drug for preventing or treating osteonecrosis of the femoral head caused by hormones. According to the required preparation, it also includes a pharmaceutically acceptable, non-toxic carrier or diluent. Such diluents are distilled water, physiological sodium chloride or phosphate buffer saline, glucose solution, etc. Such pharmaceutically acceptable carriers can be buffers, emulsifiers, suspending agents, stabilizers, preservatives, excipients, fillers, coagulants and modifiers, surfactants, dispersants or defoaming agents. In addition, the pharmaceutical composition or preparation may also include other carriers, adjuvants or non-toxic, non-therapeutic stabilizers, etc. The pharmaceutical composition may also include large, slowly metabolized macromolecules such as proteins, polysaccharides such as chitosan, polylactic acid, polyglycolic acid and copolymers (such as, for example, latex-functionalized agarose (TM), agarose, cellulose, etc.), polyamino acids, amino acid copolymers and lipid aggregates. The dosage form of the pharmaceutical composition of the present invention is tablets, capsules, granules, pills, oral liquids or injections. The drugs of the present invention can be administered into the body by known methods. The administration route is enteral administration or parenteral administration. The parenteral administration method is, for example, systemic delivery via intravenous injection or local injection into the tissue of interest. Optionally, administration is carried out via intravenous, transdermal, intranasal, mucosal or other delivery methods. The effective dose of the drug for preventing or treating steroid-induced osteonecrosis of the femoral head is 5 mg / kg - 15 mg / kg. Example 3 Use of a drug for preventing or treating steroid-induced osteonecrosis of the femoral head in the preparation of a drug for preventing or treating steroid-induced osteonecrosis of the femoral head. Specifically, steroid-induced osteonecrosis of the femoral head is osteonecrosis of the femoral head caused by the application of supra-physiological doses of glucocorticoids. The above-disclosed are only the preferred embodiments of the present invention. Of course, the scope of the rights of the present invention cannot be limited thereby. Therefore, equivalent changes made according to the claims of the present invention still fall within the scope covered by the present invention.

Claims

1. A drug for preventing or treating steroid-induced osteonecrosis of the femoral head, characterized in that, It includes the active ingredient cyclocophorol.

2. The drug for preventing or treating steroid-induced osteonecrosis of the femoral head according to claim 1, characterized in that, The drug for preventing or treating steroid-induced osteonecrosis of the femoral head is an inhibitor of CTSK protein expression in the femoral head.

3. A pharmaceutical composition, characterized in that, It includes an effective dose of the drug for preventing or treating steroid-induced osteonecrosis of the femoral head as claimed in claim 1 or 2 and a pharmaceutically acceptable carrier.

4. The pharmaceutical composition according to claim 3, characterized in that, The carrier includes one or more of a buffer, an emulsifier, a suspending agent, a stabilizer, a preservative, an excipient, a filler, a coagulant and a conditioner, a surfactant, a dispersant or an antifoaming agent.

5. The pharmaceutical composition according to claim 3, characterized in that, It also includes a pharmaceutically acceptable diluent, and the diluent is one of distilled water, physiological sodium chloride or phosphate buffered saline, and glucose solution.

6. The pharmaceutical composition according to any one of claims 3-5, characterized in that, The administration mode of the pharmaceutical composition is gastrointestinal administration or parenteral administration.

7. The pharmaceutical composition according to claim 3, characterized in that, The dosage form of the pharmaceutical composition is one of tablets, capsules, granules, pills, oral liquids or injections.

8. The pharmaceutical composition according to claim 3, characterized in that, The dosage of the drug for preventing or treating steroid-induced osteonecrosis of the femoral head is 5 mg / kg - 15 mg / kg.

9. Use of the drug for preventing or treating steroid-induced osteonecrosis of the femoral head according to claim 1 in the preparation of a drug for preventing or treating steroid-induced osteonecrosis of the femoral head.

10. The use according to claim 9, characterized in that, The steroid-induced osteonecrosis of the femoral head is osteonecrosis of the femoral head caused by the application of super-physiological dose of glucocorticoid.

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