| Background:Breast cancer is the most common malignancy among women worldwide.It is the first and second leading cause of new malignant tumors and death in women.Hormone receptor positive breast cancer is a subtype of breast cancer.Its molecular phenotype is positive for estrogen receptor(ER)and progesterone receptor(PR),accounting for more than 70%of all breast cancer.Besides surgery,chemotherapy and radiotherapy,endocrine therapy is an important treatment for this type of breast cancer.Patients need to take endocrine drugs for at least 5 years.Aromatase inhibitors(AIs)is widely used in the treatment of postmenopausal hormone receptor positive breast cancer patients.Among them,the third generation of AIs(letrozole,anastrozole,exemestane)is the first-line medication for postmenopausal breast cancer patients.It can selectively inhibit aromatase,effectively reduce the estrogen level in vivo,reduce the stimulation of estrogen on tumor cells,and reduce the local recurrence and metastasis rate.However,the adverse reactions caused by long-term use of AIs have attracted more and more attention.One of the most common adverse reactions is aromatase inhibitor associated bone loss(AIBL).In addition to the decrease of bone mineral density,patients can also have the performance of bone pain or joint pain,and even fracture.This adverse reaction seriously affects the quality of life of patients and the compliance of breast cancer treatment.Some patients even stop taking drugs,which increases the psychological burden of patients.At present,there is no exact and effective treatment for AIBL.Calcium supplement and other basic treatments are common in western medicine.Bisphosphonates and RANKL inhibitors are also used in the treatment of RANKL in recent years,but the curative effect is not exact.Traditional Chinese medicine believes that AIBL should belong to the category of"bone flaccidity" and "bone arthralgia".To summarize and analyze the drug use pattern of TCM for AIBL in the real world,to analyze the characteristics of TCM evidence,to provide a theoretical basis for clinical drug use,and to provide a data base for TCM theory.In addition,the formula of Beneficial Kidney and Healthy Bone is an effective formula developed by Professor Wang Xiaomin of Beijing Hospital of Traditional Chinese Medicine,Capital Medical University.The whole prescription is made up of 12 kinds of traditional Chinese medicine,such as Rehmannia glutinosa,cypress root and Cyperus adenosus.The method is to nourish kidney and strengthen bones and regulate liver and dredge collaterals,so as to improve bone loss and bone joint symptoms caused by aromatase inhibitor treatment in breast cancer patients.The preliminary clinical study shows that the "Yi Shen Jian Gu Fang" can reduce the pain and pain of aromatase inhibitors caused by aromatase inhibitors in breast cancer patients,and improve the quality of life.Therefore,with the help of animal models and basic experimental methods,it is of great significance to deeply explore the effect of Yishen Jiangu recipe on bone structure and bone metabolism,and explore its mechanism,so as to provide basic research data for Yishen Jiangu recipe in the treatment of AIBL.Part IAim of the study:To evaluate the effects of Yishen Jiangu recipe on bone structure and bone metabolism in bilateral ovariectomy+anastrozole model rats,and to explore its mechanism.Methods:Animal experiments to explore the mechanism of Yishen Jiangu recipe in the treatment of bone loss in double castrated rats.During the model administration period,the body weight of the rats in each group increased by castration,and the increase in body weight of the rats after bilateral ovariectomy was more obvious.After 12 weeks of administration,the body weight of rats in each group receiving bilateral ovarian surgery was significantly higher than that in the sham-operated group.Micro-CT:Bone volume fraction,mean thickness of trabecular bone,bone surface area to bone volume ratio,and structural pattern index were decreased in bilateral ovariectomy and double castration groups compared with sham operation group.H&E staining and Masson staining:Compared with the sham-operated group,the number and density of trabecular bone in the cancellous bone at the upper end of the tibia in the bilateral ovariectomy group and the double castration group were significantly reduced,and the thickness of the trabecular bone became thinner.Compared with the double castration group,after treatment with traditional Chinese medicine,the number and thickness of trabecular bone in the low-dose Yishen Jiangu recipe group and the high-dose group of Yishen Jiangu recipe also increased compared with the double castration group.Western Blot:The relative expression of opg/rankl protein in the lumbar spine of the rats in the bilateral ovariectomy group and the rats in the double modeling group was significantly lower than that in the sham operation group.After treatment,the relative expression of opg/rankl protein in the low-dose Yishen Jiangu recipe group and the high-dose Yishen Jiangu group was significantly higher than that in the double castration group.PCR:The relative expression of opg/rankl mRNA in the lumbar spine of the rats in the bilateral ovariectomy group and the rats in the double modeling group was significantly lower than that in the sham operation group.The relative expression of opg/rankl mRNA in the high-dose bone group was higher than that in the double castration group.Bone metabolism indexes and immune inflammatory factors:the serum OCN content of the bilateral ovariectomy group was lower than that of the sham operation group,and the serum OCN content of the low-dose Yishen Jiangu recipe group was significantly higher than that of the bilateral ovariectomy group.In terms of serum TNF-α,the content of Yishen Jiangu recipe in the high-dose group was lower than that in the double castration group.In terms of serum TGF-β,the serum content of the rats in the middle-dose Yishen Jiangu recipe group was significantly lower than that in the bilateral ovariectomy group and the double castration group.In terms of serum IL-1 and IL-17,no significant differences were observed between the groups of rats.Results:To explore the mechanism of Yishen Jiangu Recipe on bone loss in double ovariectomized rats.During the modeling and administration period,the weight of rats in each group increased,and the weight of rats after bilateral ovariectomy increased more significantly.After 12 weeks of administration,the weight of rats in each group undergoing bilateral ovarian surgery was significantly higher than that in the sham operation group.Micro CT:compared with the sham operation group,the bone volume fraction,average thickness of bone trabeculae,bone surface area,bone volume ratio,structural pattern index and bone mass index of bilateral ovariectomy group and double castration group decreased.H&E staining and Masson staining:the number and density of trabeculae in cancellous bone at the upper end of tibia in bilateral ovariectomy group and double castration group were significantly lower than those in sham operation group,and the thickness of trabeculae became thinner.Compared with the double castration group,the number and thickness of bone trabeculae in the low-dose group and the high-dose group were also increased compared with the double castration group.Western blot:the relative expression of OPG/RANKL protein in lumbar spine of rats in bilateral ovariectomy group and double model rats was significantly lower than that in sham operation group.After treatment,the relative expression of OPG/RANKL protein in low-dose group and high dose group was significantly higher than that in double castration group.PCR:the relative expression of OPG/RANKL mRNA in lumbar spine of rats in bilateral ovariectomy group and double model rats was significantly lower than that in sham operation group.After treatment,the relative expression of OPG/RANKL mRNA in low-dose group and high-dose group was higher than that in double castration group.Immune inflammatory factors:the content of serum TRACP in the medium dose group was higher than that in the bilateral ovariectomy group,the content of serum OCN in the bilateral ovariectomy group was lower than that in the sham operation group,and the content of serum OCN in the low-dose group was significantly higher than that in the bilateral ovariectomy group.Serum TGF-β,the serum content of rats in the high-dose group was significantly lower than that in the bilateral ovariectomy group and the double castration group.Serum TNF-α,the rats in bilateral ovariectomy group were significantly lower than those in sham operation group,and the high-dose group of traditional Chinese medicine was lower than that in double castration group.Serum IL-1,IL-1 in the medium dose group was significantly lower than that in the double castration group.No difference in serum IL-17A was observed in each group.Conclusions:Bone loss is obvious in rats after bilateral ovariectomy.Yishen Jiangu recipe has a protective effect on bone loss caused by anastrozole.It can increase the number and density of trabecular bone and thicken the thickness of trabecular bone.By regulating the RANKL-RANKL-OPG axis,regulating the levels of TNF-α and TGF-β inflammatory factors plays a role in the treatment of AIBL.Part ⅡAim of the study:The data of breast cancer patients treated in Beijing Chinese Medicine Hospital affiliated to Beijing Chinese Medicine Hospital were collected and analyzed.Data mining methods were used to make statistical analysis of the important prescriptions of the visiting patients.The diagnosis and treatment of the aromatase inhibitors related bone loss in the real world were discussed,providing theoretical basis and data basis for clinical medication.Methods:According to the research platform of Beijing Chinese Medicine Hospital affiliated to Capital Medical University,the information of breast cancer patients who visited the oncology outpatient clinic from January 1,2019 to October 31,2021 was obtained.According to the inclusion and exclusion criteria,the patients with aromatase inhibitor related bone loss were selected as the research objects and the data were extracted.The four gases,five flavors,efficacy and meridian tropism of the prescription were analyzed by Excel software.SPSS26.0 to analyze the patient’s age and other data,measure the Apriori algorithm and systematic clustering in SPSS modeler 18.0 software to analyze the association rules and medication rules of traditional Chinese medicine.Results:According to the inclusion and exclusion criteria,184 eligible patients were finally included with a total of 184 visits.The average age of the patients was 63.2±8 years old,including 71 taking anastrozole,60 letrozole and 53 exemestane.①The most common TCM syndrome types are positive deficiency and toxin syndrome,liver depression and spleen deficiency syndrome,phlegm and blood stasis syndrome,Qi deficiency and blood stasis syndrome and qi stagnation and blood stasis syndrome.②All 184 prescriptions involved 298 traditional Chinese medicines.The top five drugs in use frequency and frequency were Poria cocos,bupleurum,Hedyotis diffusa,Atractylodes macrocephala and licorice.③The four Qi of drugs are mainly warm and flat drugs,followed by cold and slightly cold drugs,and the febrile drugs are the least.The five flavors of traditional Chinese medicine are mostly sweet,bitter and pungent drugs,and the liver meridian is the most,followed by lung meridian,spleen meridian,stomach meridian,heart meridian and kidney meridian.④In terms of the efficacy of traditional Chinese medicine,the most frequently used drugs are drugs for promoting blood circulation and removing blood stasis,drugs for Invigorating Qi,drugs for clearing away heat and detoxification,and drugs for relieving surface.⑤According to the association rules of traditional Chinese medicine,the drug combination with the highest confidence is Bupleurum-Yujin(86.54%),and the drug combination with the highest support is Poria cocos→Atractylodes macrocephala and Hedyotis diffusa(36.41%).⑥According to the cluster analysis and clinical application of traditional Chinese medicine,traditional Chinese medicine can be divided into four categories:Poria cocos,Atractylodes macrocephala,Prunella vulgaris,oyster,Hedyotis diffusa,Scutellaria barbata and peony bark;The second category:sour jujube kernel,Poria;The third category:Radix Paeoniae Rubra,Achyranthes bidentata,radix curcumae,Rhizoma Corydalis,Rhizoma Cyperi,licorice,Radix Paeoniae Alba,Radix Bupleuri,Angelica sinensis,Ligusticum chuanxiong and poria cocos;The fourth category:Astragalus membranaceus,Codonopsis pilosula,Pinellia ternata,tangerine peel,arrowhead mushroom,Amomum villosum,Scutellaria baicalensis.Conclusions:Poria cocos,Radix Bupleuri,Hedyotis diffusa,Rhizoma Atractylodis Macrocephalae and Radix Glycyrrhizae have the highest frequency of traditional Chinese medicine in the treatment of AIBL.From the perspective of drug efficacy,they are mainly drugs for promoting blood circulation and removing blood stasis,invigorating qi and clearing away heat and detoxification.The drug combinations with the highest confidence and support are Radix Bupleuri Yujin,tuckahoe Atractylodes Macrocephalae and Hedyotis diffusa,which reflect the treatment principle of traditional Chinese medicine in the treatment of AIBL from tonifying the kidney,regulating the liver,removing blood stasis and dredging collaterals.The most traditional Chinese medicine for the treatment of AIBL is the drugs that return to the liver meridian,mainly sweet and bitter drugs,and warm and flat drugs are more common.Through cluster analysis,the traditional Chinese medicine for the treatment of AIBL is divided into four categories:Soothing Liver and clearing heat,regulating qi and dredging collaterals,nourishing heart and calming mind,supplementing qi and detoxifying,which reflects the compatibility characteristics of traditional Chinese medicine treatment. |
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