Application of quercidic acid in preparation of medicine or medicine composition for preventing or treating glucocorticoid excess related diseases or symptoms

Abstract

The invention discloses application of quercidic acid in preparation of a medicine or a medicine composition for preventing or treating diseases or symptoms related to excessive glucocorticoid. According to the application disclosed by the invention, the protective effect of the quercidic acid on the GIONFH is verified through a preclinical model, and evidence that the quercidic acid can be applied to prevention or treatment of the GIONFH is provided. Animal experiments prove that the quercidic acid can inhibit methylprednisolone-induced rat GIONFH, and the action mechanism is related to inhibition of osteoclasts. The medicine or the medicine composition described by the invention can obviously improve the formation of necrotic fossa in femoral head of GIONFH, bone loss of bone trabecula, CTSK positive cell expression, osteoclast formation, bone resorption protein expression and osteoclast overactivity at a lower dosage, and provides a potential prevention and treatment scheme for treatment of GIONFH.

Description

Technical Field

[0001] This application belongs to the field of biomedical technology, specifically relating to the use of quercetin in the preparation of medicaments or pharmaceutical compositions for the prevention or treatment of diseases or conditions related to glucocorticoid overdose. Background Technology

[0002] GIONFH is a pathological process caused by the long-term or excessive use of glucocorticoids, resulting in the death of cellular components within the femoral head. The main symptoms of GIONFH are hip pain and limited mobility. Disease progression can lead to femoral head collapse and subsequent hip arthritis, requiring joint replacement in the late stages. Current treatment methods still have limitations. Surgical treatments such as core decompression, iliac bone grafting, and osteotomy have drawbacks including high risks, long postoperative recovery periods, and poor patient compliance. Even with joint replacement, because most patients are young or middle-aged, revision surgery is often necessary after the initial lifespan of the procedure.

[0003] In a normal femoral head, osteoblasts and osteoclasts are coupled, maintaining a dynamic balance between bone formation and resorption. Supraphysiological doses of glucocorticoids lead to decreased osteoblast bone formation and reduced bone strength, while osteoclast lifespan is prolonged and bone resorption activity is enhanced. In GIONFH, osteoclast bone resorption exceeds osteoblast bone formation, resulting in increased bone loss and microfractures, a key factor driving femoral head collapse. Currently, there is considerable research on osteoclast-inhibiting therapy for GIONFH; however, widely accepted safe and effective drugs are still lacking.

[0004] Osteoclasts (OCs) are multinucleated cells with bone resorption function derived from the mononuclear-macrophage system. The precursor of osteoclasts is bone marrow macrophages (BMMs), whose survival depends on macrophage-colony stimulating factor (M-CS). Receptor activator of nuclear factor-κB ligand (RANKL) can activate the nuclear factor-κB receptor (RANK) on the surface of bone marrow mesenchymal stem cells (BMMs), leading to a series of intracellular signal transductions. Among these, nuclear factor-activated T cell 1 (NFATc1) is the main transcription factor. Its activation induces the expression of osteoclast formation and bone resorption markers such as tartrate-resistant acid phosphatase (TRAP), matrix metalloproteinase 9 (MMP9), and cathepsin K (CTSK), thus playing a role in bone resorption.

[0005] Currently, osteoclast inhibition therapy has emerged as a potential treatment strategy for GIONFH (steroid-induced femoral head necrosis), but safe and effective drugs are still lacking. Bisphosphonates can inhibit osteoclasts, but they also inhibit bone formation and angiogenesis, and can lead to mandibular osteonecrosis. Furthermore, their clinical efficacy in GIONFH is controversial, with reported side effects including mandibular osteonecrosis, atypical subtrochanteric fractures, and rebound after drug withdrawal. Safe and effective drugs targeting osteoclast activity in GIONFH are still lacking. Denosumab, a RANKL monoclonal antibody, blocks the binding of RANKL to RANK, thereby inhibiting osteoclast differentiation and bone resorption. Although clinical reports suggest it can prevent the progression of SIONFH, there is a risk of vertebral rebound fractures after drug withdrawal.

[0006] Traditional Chinese medicine has been clinically validated in slowing the progression of GIONFH and preventing femoral head collapse, making it a valuable resource for developing safe and effective drugs for the prevention and treatment of GIONFH. Gentiana macrophylla is a commonly used drug in orthopedic treatment, showing certain efficacy against osteoarthritis and other diseases. Quercetin is a triterpenoid saponin compound derived from Gentiana macrophylla; studies have reported its anti-aging and antioxidant properties. Previous research by the applicant found that quercetin can inhibit RANKL-induced osteoclast formation and bone resorption, and improve bone loss in osteoporotic mice. However, no studies have yet confirmed the role of quercetin in the prevention and treatment of GIONFH. Summary of the Invention

[0007] The purpose of this application is to provide the use of quercetin in the preparation of drugs for the prevention or treatment of glucocorticoid-induced femoral head necrosis, thereby solving the problem of the lack of effective drugs for the prevention or treatment of GIONFH in the prior art.

[0008] Furthermore, the drug or drug composition may perform one or more of the following effects:

[0009] 1) The drug is used to inhibit the formation of necrotic fossae in the femoral head of GIONFH patients;

[0010] 2) The drug is used to inhibit bone loss of the trabecular bone in the femoral head of GIONFH patients;

[0011] 3) The drug was used to inhibit the expression of CTSK-positive cells in the femoral head of GIONFH patients;

[0012] 4) The drug is used to inhibit osteoclast formation and bone resorption protein expression in the femoral head of GIONFH patients;

[0013] 5) The drug is used to inhibit the excessive activation of osteoclasts in the femoral head of GIONFH patients.

[0014] Furthermore, the dosage form of the drug or drug composition is one of the following: tablets, granules, pills, oral liquids, injections, powders, solid oral suspensions, sprays, suppositories, patches, capsules, sustained-release capsules, controlled-release capsules, and sublingual tablets.

[0015] Furthermore, the spray is a nasal spray.

[0016] Furthermore, the injection is an intravenous injection, an intramuscular injection, or a subcutaneous injection.

[0017] Furthermore, the drug or pharmaceutical composition includes quercetin and a pharmaceutically acceptable carrier, which includes one or more of lactose, hydroxypropyl methylcellulose, polymer microspheres, nanoparticles, liposomes, and micelles.

[0018] Furthermore, the administration route of the drug or drug composition includes one or more of the following: gastrointestinal administration, rectal administration, sublingual administration, and topical administration.

[0019] Furthermore, diseases or conditions related to excessive glucocorticoids include glucocorticoid-induced avascular necrosis of the femoral head, glucocorticoid-induced osteoporosis, impaired fracture healing, or other bone metabolic disorders.

[0020] The present invention also provides the use of quercetin in combination with anti-osteoporosis drugs or bone regeneration drugs in the preparation of drugs or pharmaceutical compositions for the prevention or treatment of glucocorticoid-induced femoral head necrosis.

[0021] Compared with the prior art, the present invention has the following advantages:

[0022] 1. This invention has demonstrated through animal experiments that quercetin can inhibit methylprednisolone-induced GIONFH in rats, and the mechanism of action is related to the inhibition of osteoclasts.

[0023] 2. Previous experiments using cell and animal models have confirmed that quercetin can significantly improve the formation of necrotic lacunae in the femoral head of rats at low doses, inhibit excessive activation of osteoclasts, reduce the expression of osteoclast formation and bone resorption proteins, and reduce excessive bone resorption in the femoral head.

[0024] 3. The present invention demonstrates that quercetin has the ability to inhibit osteoclast overactivity in the GIONFH model, which may delay disease progression, postpone hip replacement, and improve the quality of life of patients.

[0025] 4. The drug described in this invention can significantly improve the formation of femoral head necrosis lacunae, bone loss of trabeculae, expression of CTSK positive cells, osteoclast formation and bone resorption protein expression, and osteoclast overactivation in GIONFH at a low dose, providing a potential prevention and treatment option for the treatment of GIONFH.

[0026] 5. This invention adjusts the dosage form, dosage, and route of administration of the drug composition according to the patient's specific condition and physical characteristics to achieve individualized treatment, thereby improving treatment efficacy and reducing side effects. Attached Figure Description

[0027] Figure 1A. Flowchart of the quercetin intervention experiment in rats; B. Weekly weight changes of rats in each group; Intramuscular injection (IM); Intraperitoneal injection (IP); Region of interest (ROI); Vehicle; Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH); Normal saline (NS)

[0028] Figure 2 A. Frontal section images of bilateral femoral heads of rats and 3D images of regions of interest (ROIs) reconstructed from scans; B. Bone parameters of the left femoral head ROI in each group of rats, n=5; C. Bone parameters of the right femoral head ROI in each group of rats, n=5; D. Bone parameters of all femoral head ROIs in each group of rats, n=10; BV / TV: bone volume fraction; Tb.N: number of trabeculae; Tb.Th: trabecular thickness; Tb.Sp: trabecular dispersion.

[0029] Figure 3 A. Typical image of rat femoral head stained with HE; B. Quantitative analysis results of the proportion of trabecular bone necrosis lacunae in HE staining; C. Quantitative analysis results of trabecular bone volume fraction in HE staining;

[0030] Figure 4 A. Representative and pseudo-color images of rat femoral head CTSK immunohistochemistry (far right); B. Quantitative analysis results of CTSK(+) perimeter on the surface of bone trabeculae in CTSK immunohistochemical staining; C. Quantitative analysis results of CTSK(+) surface area in the bone marrow cavity in CTSK immunohistochemical staining;

[0031] Figure 5 Molecular docking diagram showing the binding modes of quercetin to RANK and NFATc1 proteins;

[0032] Figure 6 A. Representative Western blot images; B. Quantitative analysis results of relative expression of RANK protein; C. Quantitative analysis results of relative expression of NFATc1 protein; D. Quantitative analysis results of relative expression of MMP9 protein; E. Quantitative analysis results of relative expression of CTSK protein;

[0033] Figure 7A. Representative images of TRAP staining; B. Number of osteoclasts with positive TRAP staining and ≥3 cell nuclei in each group; C. Perimeter of a single osteoclast with positive TRAP staining and ≥3 cell nuclei in each group; D. Surface area of a single osteoclast with positive TRAP staining and ≥3 cell nuclei in each group. Detailed implementation mode

[0034] The present application will be further described below in conjunction with embodiments, but is not limited thereto.

[0035] Materials, reagents, etc. used in the following embodiments can be obtained from commercial channels without special instructions.

[0036] Example 1:

[0037] This example provides the preparation of a rat GIONFH model, intervention tests with different doses of gallic acid, and verification. The main steps are as follows:

[0038] (1) Grouping and feeding of experimental animals

[0039] A total of 20 9-week-old SPF-grade Sprague Dawley (SD) rats, all female, were selected. All animals were purchased from the Animal Experiment Center of Guangzhou University of Chinese Medicine (SCXK[Guangdong]2013 - 0034), and the animal certificate number was 44005800008479. This animal experiment was approved by the Animal Experiment Ethics Review Committee of this university (20190722001). The rats were weighed and numbered, and randomly divided into a solvent control group, a GIONFH model group, a low-dose gallic acid intervention group (2.5 mg / kg), and a high-dose gallic acid intervention group (5 mg / kg), with 5 rats in each group. Rats in the same group were placed in the same cage, fed with ordinary feed, allowed to freely eat and drink water, and kept under 24-hour cyclic light. The body weight was recorded weekly, and the rats were modeled after one week of adaptive feeding.

[0040] (2) GIONFH modeling and gallic acid intervention

[0041] In the GIONFH model group, rats were weighed before modeling, and the required amount of methylprednisolone was calculated based on their weight. The dosage of methylprednisolone was controlled at 20 mg / kg, and it was diluted with sterile saline and injected intramuscularly into the buttocks. The low-dose quercetin intervention group and the high-dose quercetin intervention group received intraperitoneal injections of different doses of quercetin (2.5 and 5 mg / kg), respectively, in addition to the methylprednisolone injections as in the GIONFH model group. The solvent control group received intramuscular injections of sterile saline into the buttocks. The injections were administered on days 1 to 3 of each week, 24 hours apart, followed by a 4-day rest period. This process was repeated in weeks 2 and 3, for a total of 9 injections, followed by a 4-week intervention break. At the end of week 7, all rats were euthanized under CO2 anesthesia, and femoral tissue was harvested. The femoral heads were removed bilaterally and preserved in 4% paraformaldehyde, while the remaining bone tissue was stored at -80°C for later use.

[0042] Experimental procedure and changes in rat body weight are as follows: Figure 1 As shown, where Figure 1 A is the flowchart of the quercetin intervention experiment in rats. Figure 1 B shows the weekly weight changes of rats in each group. As can be seen from the figure, quercetin intervention did not significantly affect the weight changes of GIONFH rats.

[0043] (3) Micro-CT scan to assess the effect of quercetin on bone structure damage.

[0044] Rat femoral head specimens were collected and fixed with 4% paraformaldehyde for 48 hours before micro-CT scanning. The resolution was set to 12 μm pixels, 0.5 mm AI filter, and 1 K resolution. Reconstruction was performed using the accompanying software. A continuous layer with a height of 0.3 mm and a radius of 0.65 mm was selected below the femoral head epiphysis in the coronal plane as the region of interest (ROI). Various bone parameters of the ROI were obtained using the accompanying software, including bone volume / tissue volume (BV / TV), trabecular bone number (Tb.N), trabecular bone thickness (Tb.Th), and trabecular separation (Tb.Sp).

[0045] Scan results as follows Figure 2 As shown, Micro-CT reconstruction revealed that quercetin improved intrafemoral osteolysis in the femoral head of GIONFH rats. Among other things, Figure 2A shows the frontal section image of the bilateral femoral heads of rats and the 3D image of the region of interest scan and reconstruction. It shows that the trabecular bone structure of rats in the solvent control group is dense, while the trabecular bone structure of the GIONFH model group is relatively sparse. The trabecular bone structure of rats in the intervention groups with different doses of quercetin becomes dense, and this is more obvious in the high-dose intervention group. Figure 2 B represents the quantitative analysis results of ROI bone parameters in the left femoral head of each group of rats. Statistical analysis showed that quercetin dose-dependently increased the bone volume fraction (p<0.05) and the number of trabeculae in the left femoral head of GIONFH rats (p<0.05), and decreased the trabecular separation (p<0.05), but had no significant effect on trabecular thickness. n=5. Figure 2 C represents the ROI bone parameters of the right femoral head in each group of rats. Statistical analysis showed that quercetin dose-dependently increased the bone volume fraction (p<0.05) and the number of trabeculae (p<0.05) in the right femoral head of GIONFH rats, and decreased the trabecular separation (p<0.05), but had no significant effect on trabecular thickness (Tb.Th). n=5. Figure 2 D represents the quantitative analysis results of ROI bone parameters in the bilateral femoral heads of rats in each group. Statistical analysis showed that quercetin dose-dependently increased the trabecular volume fraction (BV / TV) and the number of trabecular bones (Tb.N) in the bilateral femoral heads of GIONFH rats (p<0.05), and decreased trabecular separation (Tb.Sp) (p<0.05), but had no significant effect on trabecular thickness (Tb.Th). n=10. * indicates statistically significant differences (P<0.05).

[0046] (4) HE staining to assess the effect of quercetin on necrotic pit formation and bone structure damage.

[0047] After femoral head fixation, the tissue was dehydrated using a gradient of alcohol, decalcified with 10% EDTA, and then dehydrated again using a gradient of alcohol. Xylene was used for clearing, followed by paraffin embedding. Serial sections were prepared using a microtome, dewaxed, and rehydrated. The sections were then stained with hematoxylin and eosin, dehydrated with alcohol, cleared with xylene, mounted, and scanned. The ratio of the number of necrotic lacunae formed by necrotic osteocytes to the number of osteocyte lacunae in the femoral head was observed and counted using slide reading software as the necrotic lacunae rate. The bone volume (BV) / tube volume (TV) ratio of trabecular bone was also measured to assess bone loss.

[0048] The results are as follows Figure 3 As shown, HE staining revealed that quercetin improved the reduction of necrotic lacunae and trabeculae in the femoral head of GIONFH rats. Among these, Figure 3 Typical HE staining images of the femoral head of rats in group A show that the solvent control group has fewer necrotic pits and normal trabeculae, while the GIONFH model group has increased formation of necrotic pits in the femoral head (indicated by black arrows) and sparse trabeculae. After quercetin intervention, the number of necrotic pits decreased and the number of trabeculae increased. Figure 3B shows the quantitative analysis results of the proportion of necrotic lacunae in trabecular bone stained with HE. Statistical analysis showed that GIONFH modeling significantly increased the proportion of necrotic lacunae, while quercetin intervention dose-dependently reduced the formation of necrotic lacunae in the femoral head of GIONFH rats (p<0.05). Figure 3 Figure C shows the quantitative analysis results of trabecular bone volume fraction in HE staining. Statistical analysis showed that GIONFH modeling significantly reduced trabecular bone volume fraction (p<0.05), while quercetin intervention dose-dependently increased the trabecular bone volume fraction in the femoral head of GIONFH rats (p<0.05). In the figure, n=3, * indicates statistically significant difference P<0.05.

[0049] (5) Immunohistochemical assessment of the effect of quercetin on CTSK expression in osteoclasts

[0050] Rat femoral head sections were dewaxed with xylene, and after antigen retrieval, non-specific site blocking was performed using fetal bovine serum. The blocked sections were incubated overnight at 4°C with CTSK primary antibody, followed by incubation at room temperature for 1 hour the next day with secondary antibody. DAB staining was performed, followed by HE counterstaining. After mounting, the sections were scanned, and the perimeter of CTSK(+) cells adhering to the medullary cavity of the femoral head and the area of ​​CTSK(+) cells in the medullary cavity were observed and measured using slide reading software to assess osteoclast activation. In the figure, n=3, * indicates statistically significant difference P<0.05.

[0051] The results are as follows Figure 4 As shown, CTSK immunohistochemistry revealed that quercetin improved osteoclast formation in the femoral head of GIONFH rats. Among other things, Figure 4 Representative immunohistochemical images and pseudocolor images (far right) of the rat femoral head CTSK in the solvent control group show that there are fewer CTSK(+) osteoclasts on the surface of the trabecular bone in the femoral head and in the medullary cavity, while the number of CTSK(+) osteoclasts in the femoral head of the GIONFH model group is significantly increased. Quercetin intervention dose-dependently inhibits the formation of CTSK(+) osteoclasts. Figure 4 B shows the quantitative analysis results of the CTSK(+) perimeter on the trabecular surface in CTSK immunohistochemical staining. Statistical analysis showed that GIONFH modeling significantly increased the ratio of the perimeter covered by CTSK(+) on the trabecular surface to the total trabecular surface perimeter (p<0.05), while quercetin intervention dose-dependently decreased the ratio of the perimeter covered by CTSK(+) on the trabecular surface to the total trabecular surface perimeter (p<0.05). Figure 4Figure C shows the quantitative analysis results of CTSK(+) surface area in the bone marrow cavity after CTSK immunohistochemical staining. Statistical analysis showed that GIONFH modeling significantly increased the CTSK(+) surface area in the bone marrow cavity (p<0.05), while quercetin intervention dose-dependently decreased the CTSK(+) surface area in the bone marrow cavity (p<0.05). In the figure, n=3, * indicates statistically significant difference P<0.05.

[0052] (6) Molecular docking assessment of the effect of quercetin on the RANK / NFATc1 pathway in osteoclasts.

[0053] Download the RANK and NFATc1 structures from PDB, and the 3D structure of quercetin from Chembook. Remove structural impurities from the protein, add hydrogen atoms, and correct the charge state to ensure a proper conformation. Use AutoDock to simulate docking and view information such as binding mode, binding site, and binding energy.

[0054] Molecular docking results as follows Figure 5 As shown in Figure A, the molecular docking image demonstrates that quercetin can bind to a specific site on the RANK protein, with a score of -8.3 kcal / mol. Figure B shows the same molecular docking image, with a score of -7.8 kcal / mol.

[0055] (7) Immunoblotting assay to assess the effect of quercetin on the RANK / NFATc1 pathway in osteoclasts.

[0056] Bone tissue was ground with liquid nitrogen, and total protein was extracted using RIPA. After protein denaturation, SDS-PAGE was performed. After transfer to a membrane, the tissue was incubated overnight at 4°C with primary antibody and then incubated at room temperature for 1 hour with secondary antibody. The incubated proteins included RANK, NFATc1, MMP9, and CTSK. β-actin was set as an internal control. The gray values ​​of the exposed bands were analyzed using ImageJ and compared with the gray values ​​of the internal control protein to calculate the relative expression level of the target protein.

[0057] The results are as follows Figure 6 As shown, Western blot analysis confirmed that quercetin can inhibit the expression of the RANK / NFATc1 pathway and its downstream markers in osteoclasts of GIONFH rats. Among these, Figure 6 Representative Western blot images in group A showed that the expression levels of RANK, NFATc1, MMP9, and CTSK proteins in the femoral head of rats in the solvent control group were low, while the expression levels of RANK, NFATc1, MMP9, and CTSK proteins in the femoral head of rats in the model group were significantly increased. Quercetin intervention dose-dependently inhibited the expression of these proteins. Figure 6BE (Beta Equation) shows the quantitative analysis results of the relative expression of RANK, NFATC1, MMP9, and CTSK proteins, normalized to the GIONFH model group. Statistical analysis showed that GIONFH modeling significantly increased the expression of RANK, NFATC1, MMP9, and CTSK proteins in bone tissue (p<0.05), while quercetin intervention dose-dependently decreased the expression of RANK, NFATC1, MMP9, and CTSK proteins in the bone marrow cavity (p<0.05). In the figure, n=3, * indicates statistically significant difference (P<0.05).

[0058] (8) TRAP staining to assess the effect of quercetin on glucocorticoid-enhanced osteoclast formation.

[0059] Primary bone marrow markers (BMMs) were isolated from the hind limb long bones of 6-week-old SPF-grade C57BL / 6J mice and maintained and passaged using 30 ng / mL M-CSF. Cells were seeded into 96-well plates at a density of 8,000 cells / well. Three groups were established: a solvent group without osteoclast differentiation induction (30 ng / mL M-CSF), a group simulating GIONFH osteoclast overactivation (50 ng / mL RANKL + 10 ng / mL dexamethasone combined induction), and intervention groups receiving different doses of quercetin (5 and 10 μM). Each group had four replicates. Intervention factors were added to each group on days 1, 3, and 5. After osteoclast maturation on day 5, TRAP staining was performed. The wells were scanned using a microscopic imaging system. Cells with TRAP-positive staining and ≥3 nuclei were considered osteoclasts. The number, perimeter, and area of ​​osteoclasts in each group were analyzed using visualization software.

[0060] The results are as follows Figure 7 As shown, TRAP staining revealed that quercetin could inhibit excessive activation of GIONFH osteoclasts in an in vitro model. Among other things, Figure 7 Representative TRAP-stained images in A show that mouse primary BMMs induced a large number of osteoclasts by RANKL + dexamethasone combined, while intervention with 5 and 10 μM quercetin dose-dependently inhibited the number of osteoclasts, the perimeter of individual osteoclasts, and the surface area of ​​individual osteoclasts. Figure 7 BD quantitatively analyzed the number of TRAP-positive osteoclasts with ≥3 nuclei, the perimeter of individual osteoclasts, and the surface area of ​​individual osteoclasts in each group. The results showed that quercetin intervention significantly reduced the number of osteoclasts induced by the combined use of glucocorticoids and RANKL (p<0.05), the perimeter of individual osteoclasts (p<0.05), and the surface area of ​​individual osteoclasts (p<0.05). In the figure, n=4, * indicates statistically significant difference (P<0.05).

[0061] (9) Statistical Analysis

[0062] GraphPad statistical analysis was used. Statistical data are expressed as mean ± standard value. Each group was repeated ≥3 times. The t-test was used for comparisons between two groups, and one-way ANOVA was used for comparisons among multiple groups. The difference was considered statistically significant when p < 0.05.

[0063] Example 2:

[0064] This embodiment discloses the use of quercetin in the preparation of medicaments or pharmaceutical compositions for the prevention or treatment of diseases or conditions related to glucocorticoid overdose.

[0065] Based on the research and verification of Example 1, the use of quercetin in the preparation of drugs or pharmaceutical compositions for the prevention or treatment of glucocorticoid overdose-related diseases or conditions is determined. The drugs or pharmaceutical compositions may perform one or more of the following functions:

[0066] 1) The drug is used to inhibit the formation of necrotic fossae in the femoral head of GIONFH patients;

[0067] 2) The drug is used to inhibit bone loss of the trabecular bone in the femoral head of GIONFH patients;

[0068] 3) The drug was used to inhibit the expression of CTSK-positive cells in the femoral head of GIONFH patients;

[0069] 4) The drug is used to inhibit osteoclast formation and bone resorption protein expression in the femoral head of GIONFH patients;

[0070] 5) The drug is used to inhibit the excessive activation of osteoclasts in the femoral head of GIONFH patients.

[0071] The dosage form of the drug or drug composition may be one of the following: tablets, granules, pills, oral liquids, injections, powders, solid oral suspensions, sprays, suppositories, patches, capsules, sustained-release capsules, controlled-release capsules, and sublingual tablets. Examples include nasal sprays, intravenous injections, intramuscular injections, or subcutaneous injections.

[0072] The drug or pharmaceutical composition may include not only quercetin but also a pharmaceutically acceptable carrier, which may include one or more of lactose, hydroxypropyl methylcellulose, polymer microspheres, nanoparticles, liposomes, and micelles.

[0073] The routes of administration of drugs or drug compositions include one or more of the following: gastrointestinal administration, rectal administration, sublingual administration, and topical administration.

[0074] Diseases or conditions related to excessive glucocorticoids include glucocorticoid-induced avascular necrosis of the femoral head, glucocorticoid-induced osteoporosis, impaired fracture healing, or other bone metabolic disorders.

[0075] Quercetin can also be used in combination with anti-osteoporosis drugs or bone regeneration drugs in the preparation of drugs or drug compositions for the prevention or treatment of glucocorticoid-induced femoral head necrosis.

Claims

1. Use of quercetin in the preparation of medicaments or pharmaceutical compositions for the prevention or treatment of diseases or conditions related to glucocorticoid overdose.

2. The use as described in claim 1, characterized in that: The drug or drug composition may perform one or more of the following effects: 1) The drug is used to inhibit the formation of necrotic lacunae in the femoral head of GIONFH patients; 2) The drug is used to inhibit bone loss of trabecular bone in the femoral head of GIONFH patients; 3) The drug is used to inhibit the expression of CTSK-positive cells in the femoral head of GIONFH patients; 4) The drug is used to inhibit osteoclast formation and bone resorption protein expression in the femoral head of GIONFH patients; 5) The drug is used to inhibit the excessive activation of osteoclasts in the femoral head of GIONFH patients.

3. The use as described in claim 1, characterized in that: The dosage form of the drug or drug composition is one of the following: tablets, granules, pills, oral liquids, injections, powders, solid oral suspensions, sprays, suppositories, patches, capsules, sustained-release capsules, controlled-release capsules, and sublingual tablets.

4. The use as described in claim 3, characterized in that: The spray is a nasal spray.

5. The use as described in claim 3, characterized in that: The injectable is an intravenous injection, intramuscular injection, or subcutaneous injection.

6. The use as described in claim 1, characterized in that: The drug or pharmaceutical composition includes quercetin and a pharmaceutically acceptable carrier, said carrier including one or more of lactose, hydroxypropyl methylcellulose, polymer microspheres, nanoparticles, liposomes, and micelles.

7. The use as described in claim 1, characterized in that: The administration routes of the drug or drug composition include one or more of the following: gastrointestinal administration, rectal administration, sublingual administration, and topical administration.

8. The use as described in claim 1, characterized in that: The diseases or conditions related to glucocorticoid overdose include glucocorticoid-induced avascular necrosis of the femoral head, glucocorticoid-induced osteoporosis, fracture healing disorders, or bone metabolic diseases.

9. Use of quercetin in combination with anti-osteoporosis drugs or bone regeneration drugs in the preparation of drugs or pharmaceutical compositions for the prevention or treatment of glucocorticoid-induced femoral head necrosis.

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