A Chinese medicine combination for treating breast cancer-related skeletal muscle diseases and its preparation method

Abstract

A Chinese medicine combination for treating breast cancer-related musculoskeletal diseases, made of the following raw materials in weight: 12g of Cuscuta, 30g of Achyranthes bidentata, 15g of Eucommia bark, 9g of Fructus Corni, 15g of Fructus Lycii and 12g of Rhizoma Cyperi; its preparation method is: prepare the formula amount of Cuscuta, Achyranthes bidentata, Eucommia bark, Fructus Corni, Fructus Lycii and Rhizoma Cyperi, add 1000ml of purified water, simmer for 40 minutes, and filter out the liquid medicine; compared with the prior art, the present invention provides a medicine with the functions of nourishing the liver and kidney, balancing qi and blood, and the mutual restraint and coordination of yin and yang in the compatibility, with the characteristics of smooth drug delivery and replenishment without excess, compared with the current therapeutic drugs such as Denosumab on the market, its cost performance is extremely high, and the medication is relatively safe, without obvious toxic and side effects. Therefore, the research results will further guide the clinic, reduce unnecessary medical investment, and reduce medical expenses and the economic burden of patients.

Description

Technical Field

[0001] The present invention relates to the medical field, and in particular to a Chinese medicine combination for treating breast cancer-related musculoskeletal diseases and a preparation method thereof. Background Art

[0002] Hormone receptor-positive breast cancer is the most common subtype of breast cancer, and endocrine therapy is the main means of adjuvant and advanced treatment of hormone receptor-positive (HR+) breast cancer. At present, aromatase inhibitors are effective as adjuvant endocrine therapy for breast cancer, but the accompanying bone-related symptoms often prevent patients from persisting for a full course of treatment, which directly affects the compliance of patients with postoperative treatment and their quality of life.

[0003] Aromatase inhibitors cause musculoskeletal symptoms including osteoporosis, arthralgia, myalgia, and joint stiffness, which are called aromatase inhibitor-associated musculoskeletal syndrome (AIMSS). At present, there are no clear guidelines for the diagnosis of breast cancer AIMSS, the cause of the disease is still in the exploration stage, and there is a lack of systematic and standardized treatment plans. Western medicine treatment is mainly symptomatic, and bisphosphonates or denosumab are usually used for clinical intervention, but they have many toxic side effects and poor patient compliance.

[0004] The side effects of aromatase inhibitors are not limited to bone loss, but also include bone and joint pain. At the same time, the age span of the population using AIs is large and the physical constitutions are different. If kidney-tonifying therapy is used as a universal therapy, it can neither take into account all syndromes nor reflect the concept of "different treatments for the same disease" in traditional Chinese medicine. Summary of the invention

[0005] The technical problem to be solved by the present invention is to provide a Chinese medicine combination and a preparation method for treating breast cancer-related musculoskeletal diseases, which can effectively solve the problems raised in the above-mentioned background technology.

[0006] To solve the above problems, the technical solution adopted by the present invention is: a Chinese medicine combination for treating breast cancer-related musculoskeletal diseases, which is made of the following raw materials in parts by weight: 12 parts of Cuscuta australis, 30 parts of Achyranthes bidentata, 15 parts of Eucommia ulmoides, 9 parts of Cornus officinalis, 15 parts of Lycium barbarum and 12 parts of processed Cyperus rotundus.

[0007] As a further preferred embodiment of the present invention, the described Cuscuta seeds are 12g, Achyranthes bidentata is 30g, Eucommia ulmoides is 15g, Cornus officinalis is 9g, Lycium barbarum is 15g, and Cyperus rotundus is 12g.

[0008] Another method for preparing the Chinese medicine combination includes the above-mentioned Chinese medicine combination, preparing a formula amount of Cuscuta australis, Achyranthes bidentata, Eucommia ulmoides, Cornus officinalis, Lycium barbarum and processed Cyperus rotundus, adding 1000 ml of purified water, simmering for 40 minutes, and filtering the medicinal liquid.

[0009] Compared with the prior art, the present invention provides a Chinese medicine combination and preparation method for treating breast cancer-related musculoskeletal diseases, which has the effect of tonifying the liver and kidneys, and the yin and yang are mutually restrained and harmonized in the compatibility. Compared with the current therapeutic drugs such as denosumab on the market, it has a very high cost performance, is relatively safe to use, and has no obvious toxic and side effects. Therefore, the research results will further guide the clinic, reduce unnecessary medical investment, and reduce medical expenses and the economic burden on patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 The present invention is a flowchart of a clinical trial of an embodiment;

[0011] Figure 2 WOMAC total score, (A) changes in the combined WOMAC total score of the two subgroups, (B) changes in the WOMAC total score of the AI+OFS subgroup, (C) changes in the WOMAC total score of the AI ​​subgroup;

[0012] Figure 3 TCM syndrome score, (A) changes in TCM syndrome score of the combined two subgroups, (B) changes in TCM syndrome score of AI+OFS subgroup, (C) changes in TCM syndrome score of AI subgroup;

[0013] Figure 4 Bone density T value, (A) Changes of bone density T value of lumbar vertebrae 1-4 in the two subgroups, (B) Changes of bone density T value of lumbar vertebrae 1-4 in the AI+OFS subgroup, (C) Changes of bone density T value of lumbar vertebrae 1-4 in the AI ​​subgroup, (D) Changes of bone density T value of left femur in the two subgroups, (E) Changes of bone density T value of left femur in the AI+OFS subgroup, (F) Changes of bone density T value of left femur in the AI ​​subgroup;

[0014] Figure 5 Three levels of bone metabolism: (A) changes in 25-hydroxyvitamin D3 in the two subgroups combined, (B) changes in 25-hydroxyvitamin D3 in the AI+OFS subgroup, (C) changes in 25-hydroxyvitamin D3 in the AI ​​subgroup, (D) changes in osteocalcin in the two subgroups combined, (E) changes in osteocalcin in the AI+OFS subgroup, (F) changes in osteocalcin in the AI ​​subgroup, (G) changes in β-collagen special sequence in the two subgroups combined, (H) changes in β-collagen special sequence in the AI+OFS subgroup, (I) changes in β-collagen special sequence in the AI ​​subgroup;

[0015] Figure 6 Growth hormone levels, (A) changes in growth hormone in the two subgroups combined, (B) changes in growth hormone in the AI+OFS subgroup, (C) changes in growth hormone in the AI ​​subgroup;

[0016] Figure 7Figure 2 shows the levels of hormones related to bone metabolism: (A) changes in estradiol in the two subgroups combined; (B) changes in estradiol in the AI+OFS subgroup; (C) changes in estradiol in the AI ​​subgroup; (D) changes in testosterone in the two subgroups combined; (E) changes in testosterone in the AI+OFS subgroup; and (F) changes in testosterone in the AI ​​subgroup. DETAILED DESCRIPTION

[0017] If "and / or" or "and / or" appears in the full text, its meaning includes three parallel options. Taking "A and / or B" as an example, it includes option A, or option B, or a option in which both A and B are satisfied.

[0018] In addition, the technical solutions between the various embodiments can be combined with each other, but it must be based on the fact that ordinary technicians in the field can implement it. When the combination of technical solutions is contradictory or cannot be implemented, it should be deemed that such combination of technical solutions does not exist and is not within the scope of protection required by the present invention.

[0019] As a specific embodiment 1 of the present invention:

[0020] Long-term commitment to TCM research on AIMSS, previous studies have found that the use of kidney-tonifying method can increase the bone density of the patient's lumbar spine and femur, and can increase PINP levels and reduce β-CTX levels. However, the side effects of aromatase inhibitors are not limited to bone loss, but also include bone and joint pain; at the same time, the age span of AIs users is large, and the physique is different. If kidney-tonifying therapy is used as a universal therapy, it can neither take into account all syndromes, nor "too much tonic" for non-menopausal patients, nor reflect the concept of "different treatments for the same disease" in TCM. Therefore, Professor Chen Hongfeng, starting from the theory of traditional Chinese medicine, treats aromatase inhibitor-related musculoskeletal syndrome with liver depression and kidney deficiency, and creates a kidney-tonifying and liver-regulating empirical prescription for the treatment of AIMSS, which has significant efficacy and good repeatability, greatly broadening the ideas and suitable populations for the clinical treatment of AIMSS.

[0021] The kidney-tonifying and liver-regulating prescription is a traditional Chinese medicine combination of the present invention, and its specific composition and dosage are: 12g of Cuscuta seeds, 30g of Achyranthes bidentata, 15g of Eucommia ulmoides, 9g of Cornus officinalis, 15g of Lycium barbarum, and 12g of processed Cyperus rotundus.

[0022] Cuscuta australis is a commonly used Chinese medicine in clinical practice. It has the effects of nourishing the liver and kidneys, consolidating semen and reducing urine, stabilizing pregnancy and improving eyesight. It is mainly used to treat liver and kidney deficiency, soreness of the waist and knees, impotence and spermatorrhea.

[0023] Huai Niuxi has the effects of removing blood stasis and dredging menstruation, promoting diuresis and relieving stranguria, nourishing the liver and kidneys, and strengthening the tendons and bones. It is mainly used to treat irregular menstruation, low back and knee pain, liver and kidney deficiency, etc.

[0024] Eucommia ulmoides is sweet and warm in nature, and enters the liver and kidney meridians. It has the effects of nourishing the liver and kidneys, strengthening the tendons and bones, and calming the fetus. It can be used to treat liver and kidney deficiency, low back and knee pain, weak tendons and bones, dizziness, bleeding during pregnancy, and fetal movement disorder.

[0025] Cornus officinalis tastes sour and astringent, is slightly warm in nature, and enters the liver and kidney meridians. It has the effects of nourishing the liver and kidneys, astringing the essence and consolidating deficiency. It is mainly used to treat dizziness and tinnitus, low back and knee pain, impotence and spermatorrhea, internal heat and thirst, etc.

[0026] Lycium barbarum is sweet in taste, neutral in nature, and enters the liver and kidney meridians. It has the effects of nourishing the liver and kidneys, improving eyesight, moistening the lungs and relieving cough, and delaying aging.

[0027] Processed Cyperus rotundus is mild in nature and fragrant, pungent in taste and dispersing, slightly bitter and descending, slightly sweet and harmonious, and has the effects of soothing the liver and relieving depression, regulating qi and relieving fullness, regulating menstruation and relieving pain. It is often used in clinical practice to treat symptoms such as liver depression and qi stagnation, chest and flank distension and pain, spleen and stomach qi stagnation, abdominal distension, distension and pain, irregular menstruation, amenorrhea and dysmenorrhea. Professor Chen Hongfeng selected processed Cyperus rotundus as a blood-QI drug in his prescription, which was a brilliant idea, considering that the drug can pass through the twelve meridians. The eight meridians are divided into qi, which are responsible for all qi (the human body is dominated by qi. When qi is strong, it is strong; when qi is weak, it is weak; when qi is smooth, it is flat; when qi is reversed, it is sick; when qi is cut off, it is dead. The classics say: when you are angry, your qi goes up; when you are afraid, your qi goes down; when you are happy, your qi slows down; when you are sad, your qi disappears; when you are shocked, your qi becomes chaotic; when you think, your qi becomes stagnant; when you are tired, your qi is depleted. These are the qi of the seven emotions. With Xiangfu as the main ingredient, add ascending, descending, eliminating and replenishing drugs according to the symptoms. It can also benefit the three burners, relieve the six depressions (phlegm depression, fire depression, qi depression, blood depression, dampness depression, and food depression), and stop all kinds of pain (no pain if it is unblocked). Overall, it enhances the function of the compound to balance yin and yang, qi and blood.

[0028] Dosage and Administration: Use 1000ml of pure water, simmer for about 40 minutes, concentrate to 400ml, take once a day, warm twice a day, one hour after meals.

[0029] A randomized controlled trial was conducted to study breast cancer patients who visited the outpatient department of Longhua Hospital affiliated to Shanghai University of Traditional Chinese Medicine and received aromatase inhibitor treatment.

[0030] The patients were randomly divided into treatment group and control group

[0031] The control group was given basic treatment of Caltrate D and breast surgery prescription with modifications;

[0032] The treatment group was given the Yishen Tiaogan recipe on top of this, and the treatment lasted for 6 months.

[0033] During the follow-up period, the effects of the two treatment methods on the WOMAC scores and TCM symptom and sign scores of the patients were observed and evaluated, as well as the changes in bone density and bone metabolism-related indicators [25(OH)D3, β-CTX, OC, E2, Testo, GH] during medication. At the same time, blood routine, liver and kidney function and gynecological B-ultrasound were observed to evaluate the safety of the drugs. Results: 1. In the randomized controlled trial of Yishen Tiaogan prescription for the treatment of AIMSS, 74 patients were included in the outcome index analysis. There was no statistical difference in the general information and baseline between the treatment group and the control group (P>0.05), which was comparable.

[0034] The analysis results show:

[0035] (1) After 3 months of treatment, the total WOMAC score of the two groups was significantly reduced (P<0.05). The WOMAC pain subscale of the treatment group was significantly lower than that of the control group (P<0.05). The TCM symptom and sign scores of the two groups were significantly reduced (P<0.05). In terms of TCM syndrome efficacy, the treatment group was superior to the control group (P<0.05). There was no significant difference in bone metabolism between the two groups (P>0.05). In comparison within the two groups, the estrogen level of the control group decreased significantly after medication (P<0.05).

[0036] (2) After 6 months of treatment, the WOMAC scores of the two groups were significantly reduced (P<0.05), and the WOMAC score of the treatment group was significantly lower than that of the control group (P<0.05). The TCM symptom and sign scores of the two groups were reduced, and the scores of the treatment group were significantly lower than those of the control group (P<0.05). The bone density T value of the two groups showed a downward trend, and there was no significant difference between the two groups or within the two groups (P>0.05). The T value of the left femur bone density decreased less in the treatment group; the T value of the lumbar spine bone density decreased slightly slower in the control group. There was no significant difference in the bone metabolism level between the two groups (P>0.05). In the intra-group comparison, the estrogen level of the control group decreased significantly after medication (P<0.05). Further stratified analysis showed that the growth hormone level of the AI+OFS population in the treatment group was significantly increased compared with that before medication (P<0.05).

[0037] (3) During the treatment, no significant abnormalities in blood routine, liver and kidney function, gynecological B-ultrasound, and estradiol, as well as adverse events such as fractures, were observed in either group.

[0038] Conclusion: Yishen Tiaogan prescription is effective in treating pain, stiffness, and physical function of AIMSS. It can significantly reduce the WOMAC score of patients, improve the TCM symptoms and signs of liver and kidney deficiency, and comprehensively improve the quality of life of patients. At the same time, Yishen Tiaogan prescription has good safety.

[0039] In summary, each Chinese medicine in the Yishen Tiaogan prescription has the effect of nourishing the liver and kidneys. In terms of compatibility, yin and yang restrain and harmonize each other. In the prescription, Achyranthes bidentata nourishes the liver and kidneys and strengthens the tendons and bones, and is the monarch drug; Eucommia ulmoides nourishes the liver and kidneys and regulates Chong and Ren meridians, and Lycium barbarum nourishes the liver and kidneys, improves the essence and improves eyesight, and is the minister drug; the monarch and minister drugs cooperate to nourish the liver and kidneys and strengthen the tendons and bones; Cuscuta chinensis nourishes the liver and kidneys, stabilizes the fetus and improves eyesight, Cyperus rotundus soothes the liver and relieves depression, regulates qi and relieves pain, and Cornus officinalis nourishes the liver and kidneys, astringes the essence and consolidates the body, and all three are adjuvant drugs. Achyranthes bidentata removes blood stasis and dredges the menstruation, and Cyperus rotundus regulates qi and relieves fullness, and the two work together to regulate qi and blood. "Pain if there is no nourishment, pain if there is no smoothness" is the core pathogenesis of pain. The Yishen Tiaogan prescription achieves the purpose of analgesia by nourishing the liver and kidneys, strengthening the tendons and bones, unblocking the meridians, and unblocking the qi and blood.

[0040] As a specific embodiment 2 of the present invention: Observation on the clinical efficacy of Yishen Tiaogan prescription on AIMSS in patients with HR-positive breast cancer

[0041] 1.1 Research Methods

[0042] 1.1.1 Random Methods

[0043] 1.1.1.1 Sample size estimation

[0044] This study is a superiority clinical trial of two parallel controlled groups. The main indicator is the WOMAC osteoarthritis index, and the superiority test of the comparison of the means of the two groups. The test level α is generally 0.05 (two-sided test), and the test power Power (1-β) is 0.8 (according to α = 0.05, β = 0.2, look up the table u0.05 = 1.6449, u0.2 = 0.8417).

[0045] The recruitment period was 12 months, and the follow-up period was 6 months. The ratio of the experimental group to the control group was 1:1. The WOMAC scale consists of 24 items, divided into 3 subscales: pain (5 items); stiffness (2 items); physical function (17 items).

[0046] The mean and sample standard deviation of the pain scale in the experimental group and the control group were (63.13±75.84) vs (133.64±95.23); the mean and sample standard deviation of the stiffness scale in the experimental group and the control group were (33.00±35.60) vs (67.94±45.68); the mean and sample standard deviation of the physical function scale in the experimental group and the control group were (220.21±266.85) vs (496.83±338.21).

[0047] According to the sample size calculation formula, the pain subscale requires 54 cases per group; the stiffness subscale requires 48 cases per group; and the physical function subscale requires 38 cases per group. After comprehensive consideration of each subscale, the WOMAC scale has 54 cases per group, and the loss rate is 20%. The required sample size is 68 cases per group, and 136 subjects are ultimately required. The sample size is estimated according to the sample content estimation formula for the superiority comparison of the mean between the two groups:

[0048]

[0049] illustrate:

[0050] 1. Approximate calculation based on t distribution;

[0051] 2. Sample size correction is based on the Pooled variance method;

[0052] 3. The cut-off value Δ is 0.3 times the standard deviation of the control group.

[0053] 1.1.1.2 Randomization Scheme

[0054] SPSS26.0 statistical software was used to set fixed values, such as "20220101" to generate random numbers, and the treatment group or control group was coded according to the size of the random number, with a ratio of 1:1. The selected cases will enter the corresponding groups in order.

[0055] 1.1.2 Statistical analysis plan

[0056] The measurement data were first analyzed for normality, and the data that met the normal distribution were expressed as mean ± standard deviation. The data that do not conform to the normal distribution are expressed by the median and quartile M (P25, P75). For count data, percentage, composition ratio, and rank data are used for description.

[0057] For measurement data that conform to normal distribution, independent sample t test was used for comparison between groups, and paired sample t test was used for comparison before and after treatment in the same group; rank sum test was used for non-normal distribution. For count data, chi-square test or non-parametric test was used.

[0058] The statistical test was bilateral, with a significance level of α = 0.05, and P < 0.05 was considered statistically significant. Missing values ​​were imputed using multiple interpolation or mean substitution. All statistical analyses were performed using SPSS 26.0 software.

[0059] 1.1.2 Diagnostic criteria

[0060] 1.1.2.1 Western medicine diagnostic criteria

[0061] Referring to the 2021 Chinese Society of Clinical Oncology (CSCO) breast cancer diagnosis and treatment guidelines, all cases were clearly diagnosed with breast cancer by basic pathology and molecular pathology.

[0062] 1.1.2.2 TCM diagnostic criteria

[0063] Referring to Chapter 17 of the 2002 edition of "Guidelines for Clinical Research of New Chinese Medicines" on orthopedic system diseases, Chapter 18 on liver and kidney deficiency-related syndromes in clinical research of TCM syndromes, and Professor Chen Hongfeng's clinical experience, the syndrome differentiation standards for liver and kidney deficiency were formulated.

[0064] Main symptoms: Weak waist and knees, stiff joints, and inability to hold weight.

[0065] Secondary symptoms: depression or irritability, fear of cold and cold limbs, dizziness, tinnitus, dry mouth and throat, hot flashes and night sweats, insomnia and forgetfulness, frequent urination at night, pale or reddish tongue, white or scanty tongue coating, deep, slow, weak, or thin and stringy pulse.

[0066] Liver-kidney deficiency syndrome can be diagnosed if two main symptoms and two secondary symptoms are present.

[0067] 1.1.3 Case selection

[0068] 1.1.3.1 Inclusion criteria

[0069] (1) Aged 18 to 65;

[0070] (2) patients diagnosed with breast cancer by pathology and HR-positive by immunohistochemistry;

[0071] (3) completed surgery, chemotherapy, radiotherapy, and / or targeted therapy;

[0072] (4) had received AIs (anastrozole, letrozole, exemestane) for at least 2 months;

[0073] (5) According to TCM diagnosis, it is liver and kidney deficiency;

[0074] (6) KPS score ≥60 points;

[0075] (7) expected survival period is more than 6 months;

[0076] (8) Patients who signed the informed consent and voluntarily accepted the treatment regimen of this study.

[0077] 1.1.3.2 Exclusion criteria

[0078] (1) Bone and mineral diseases: such as hypoparathyroidism or hyperparathyroidism, osteitis deformans, osteogenesis imperfecta, osteomalacia, etc.;

[0079] (2) Diseases that affect bone metabolism: such as Cushing's syndrome, hyperthyroidism, rheumatism or rheumatoid arthritis, etc.;

[0080] (3) Use of steroid hormones or anticonvulsant drugs for more than 6 months before the study;

[0081] (4) Use of hormone replacement therapy within 6 months: such as glucocorticoids, parathyroid hormone, estrogen, etc.;

[0082] (5) had undergone limb joint surgery within 6 months;

[0083] (6) Combined with serious primary diseases of cardiovascular, liver, kidney and hematopoietic systems;

[0084] (7) Patients with obvious disease progression and new distant metastasis during the study;

[0085] (8) Psychiatric patients with cognitive impairment or mental disorders.

[0086] 1.1.3.3 Falling off, rejection criteria and treatment

[0087] (1) Dropout criteria: Subjects who have obtained informed consent and entered the randomized trial after screening but fail to complete the treatment and observation period specified in the study protocol for some reason will be treated as dropouts.

[0088] (2) Exclusion criteria: taking Chinese medicine other than that in the study; poor medication compliance, failure to take Chinese medicine as required; after enrollment, it was found that the subject did not meet the inclusion criteria and was excluded.

[0089] (3) Handling of dropouts and exclusions: Contact the subjects as much as possible through phone calls, text messages, etc., ask the reasons and record the last treatment time and completed assessment items. For cases that withdraw from the study due to adverse events, appropriate treatment measures will be given according to the actual situation. The relevant trial data of dropouts and exclusions are properly preserved, that is, archived, which is also required for the statistics of the full analysis set.

[0090] 1.1.4 Research plan

[0091] 1.1.4.1 Group medication

[0092] The patients were divided into a treatment group and a control group, and all patients took Calcitrate D routinely.

[0093] Control group: post-breast surgery prescription.

[0094] Treatment group: postoperative breast cancer prescription + kidney-tonifying and liver-regulating prescription.

[0095] 1.1.4.2 Clinical research drugs and usage

[0096] (1) Study drugs:

[0097] Prescription for post-breast surgery: Lithospermum officinale 30g, raw Astragalus membranaceus 15g, Adenophora australis 15g, Curcuma 15g, stir-fried Atractylodes macrocephala 9g, and Poria cocos 9g.

[0098] Recipe for nourishing the kidney and regulating the liver: 30g of Chinese clematis, 15g of Eucommia ulmoides, 15g of Lycium barbarum, 12g of Cuscuta australis, 12g of processed Cyperus rotundus, and 9g of Cornus officinalis.

[0099] (2) Usage and Dosage:

[0100] Patients began to take Chinese medicine decoction (prepared by the decoction room of Longhua Hospital affiliated to Shanghai University of Traditional Chinese Medicine) orally from the first day after enrollment, one dose per day, warm and taken one hour after meals twice a day in the morning and evening. The Chinese medicine treatment lasted for 3 months as a course of treatment. This study observed the clinical efficacy of 2 courses of treatment.

[0101] 1.1.4.3 Principles of combined medication

[0102] (1) Except for the experimental drugs, the use of other Chinese medicines is prohibited during the observation period.

[0103] (2) Doctors should ask patients to bring all medications they are taking during visits to check their concomitant medications. The medications that must be continued for concomitant diseases or other treatments must be recorded in the "Concomitant Medication Table" of the research medical record, including the name of the medication (or other treatment name), dosage, frequency of use, and time, so that they can be analyzed and reported in the summary.

[0104] 1.1.5 Observation indicators

[0105] 1.1.5.1 Main efficacy indicators

[0106] The WOMAC scale consists of 24 items divided into 3 subscales: pain (5 items): when walking, walking up stairs, lying in bed, sitting, lying down, and standing; stiffness (2 items): after first waking up and later in the day; physical function (17 items): using stairs, sitting up, standing, bending over, walking, getting in / out of the car, shopping, putting on / off socks, getting out of bed, lying in bed, getting in / out of the shower, sitting, getting in / out of the toilet, heavy housework, and light housework.

[0107] WOMAC scores range from 0 to 96, with higher scores indicating greater pain, stiffness, and functional limitations.

[0108] 1.1.5.2 Secondary efficacy indicators

[0109] ① TCM symptom and sign score: According to the TCM symptom and sign score table, the symptoms such as soreness of waist and knees, weakness of lower limbs, chills and cold limbs, cramps in lower limbs, increased nocturia, hot flashes and night sweats were scored before and after treatment.

[0110] Due to the lack of a standard scale for evaluating TCM symptoms of AIMSS in HR+ breast cancer patients, this study focused on the bone and joint-related clinical symptoms caused by AIs treatment. Referring to the "Technical Guidelines for Clinical Research of New Chinese Medicines for the Treatment of Primary Osteoporosis" issued by the State Food and Drug Administration in 2015, as well as Chapter 17 of the 2002 "Guidelines for Clinical Research of New Chinese Medicines" on orthopedic system diseases and Chapter 18 of the TCM syndrome clinical research content, a TCM symptom and sign scoring table was compiled. Symptoms were ranked according to primary symptoms, secondary symptoms, and combined secondary symptoms, with a total of 16 items. The score was calculated using a 4-point method of none, mild, moderate, and severe, with relevant information provided by patients and evaluated by doctors. The higher the score, the heavier the TCM symptom burden, totaling 66 points.

[0111] ② Bone mineral density test: All subjects underwent bone mineral density (BMD) testing in the Imaging Department of Longhua Hospital using dual X-ray absorptiometry (DXA). The measurement sites were lumbar vertebrae 1-4 and left femur, and the T value of bone density was calculated (testing instrument: Hologic QDR4500).

[0112] ③ Three items of bone metabolism: total 25-hydroxyvitamin D3 [25(hydroxyl)vitamin D3, 25(OH)D3], β-collagen special sequence (β-Crosslaps, β-CTX), osteocalcin (Osteocalcin, OC) (detection instrument: Roche cobas8000 fully automatic biochemical analyzer).

[0113] ④ Bone metabolism-related hormones: estradiol (Estrogen, E2), testosterone (Testosterone, Testo) (Detection instrument: Roche cobas8000 automatic biochemical analyzer)

[0114] ⑤ Estradiol (Estrogen, E2), testosterone (Testosterone, Testo) (detection instrument: Roche Cobase602 fully automatic chemiluminescence analyzer).

[0115] Note: The selection of indicators ③, ④, and ⑤ refers to the "Recommended Experimental Protocol for Bone Metabolism Biochemical Indicators" (2021 Expert Consensus).

[0116] 1.1.5.3 Safety indicators

[0117] All patients had their blood routine and liver and kidney function checked every 3 months to observe the effects of the therapeutic drugs on the hematopoietic system, liver and kidney function. The occurrence of gynecological diseases was also monitored.

[0118] 1.1.6 Observation time

[0119] According to the clinical characteristics of AIMSS and the purpose of the trial, a corresponding case observation form was designed to collect data from the cases included in the study. Relevant blood indicators and questionnaires were tested 1 day before Chinese medicine intervention, 3 months ± 14 days after treatment, and 6 months ± 21 days after treatment. At the same time, gynecological B-ultrasound and bone density tests were completed before treatment and 6 months after treatment. All data were recorded using a standardized case report form (CRF) to ensure the integrity and accuracy of the data. Clinical trial flow chart reference Figure 1

[0120] 1.2 Research Results

[0121] 1.2.1 Shedding and removal

[0122] A total of 136 AIMSS patients were included, with 68 in the treatment group and 68 in the control group. During the study, 15 patients dropped out and 13 patients were excluded. Fifteen patients were unable to or refused to come to Shanghai for follow-up due to force majeure and personal reasons and actively requested to withdraw from the study, and were treated as dropouts. Seven patients were excluded because it was difficult to adhere to taking Chinese medicine or because they took other Chinese medicines at the same time; one patient was excluded because of low white blood cell count; one patient was excluded because of recurrence of breast cancer after breast-conserving surgery; two patients were excluded because of lung metastasis and bone metastasis, respectively; two patients were excluded because of the addition of abemaciclib to avoid interference. Among the 28 patients, 17 were in the treatment group and 11 were in the control group (Table 1).

[0123] Table 1 Patients dropped out or excluded (n=28)

[0124]

[0125] The 28 patients who dropped out or were excluded were not included in the analysis of outcome indicators. Finally, 108 patients were included in the data analysis, including 51 in the treatment group and 57 in the control group. The specific distribution of patients in each group is (Table 2).

[0126] Table 2 Distribution of patients in each group (n=108)

[0127]

[0128] 1.2.2 WOMAC score

[0129] Among the 108 patients, there was no significant difference in WOMAC scores between the pre-treatment group and the control group (P>0.05). Subgroup analysis was performed using endocrine therapy regimen as a stratification condition, and the WOMAC total score and its subscale (pain, stiffness, physical function) scores showed no significant difference (P>0.05), which was comparable (Table 3).

[0130] Table 3 WOMAC score before medication (n=108)

[0131]

[0132] After 3 months of medication, the total WOMAC score of the 108 patients in the treatment group was lower than that in the control group, and the difference was statistically significant (P<0.05); further analysis of its subscales (pain, stiffness, and physical function) showed that the pain score in the treatment group was significantly lower than that in the control group (P<0.05). The endocrine therapy regimen was used as a stratification condition for subgroup analysis, and the results showed that the pain score of the AI+OFS subgroup was lower in the treatment group than in the control group (P<0.05), while in the AI ​​subgroup, there was no significant difference between the treatment group and the control group (P>0.05) (Table 4).

[0133] Table 4 WOMAC score after 3 months of medication (n=108)

[0134]

[0135]

[0136] Note: *P<0.05, the difference is statistically significant.

[0137] After 3 months of medication, the combined intra-group comparison showed that the WOMAC total scores of the treatment group and the control group decreased significantly after medication (P<0.05). Further stratified statistics showed that the WOMAC total scores of the treatment group in the AI ​​subgroup and the AI+OFS subgroup decreased significantly (P<0.05), while there was no statistically significant difference in the WOMAC total scores between the AI+OFS subgroup and the control group after medication (P>0.05) ( Figure 2 ).

[0138] After 6 months of medication, the total WOMAC score of the 108 patients in the treatment group was lower than that in the control group, and the difference was statistically significant (P<0.05). Further analysis of its subscales (pain, stiffness, and physical function) showed that in terms of pain, stiffness, and physical function, the treatment group was significantly lower than the control group (P<0.05).

[0139] Subgroup analysis was performed using endocrine therapy as a stratification condition. The results showed that in the AI+OFS subgroup or AI subgroup, the WOMAC total score and the scores of pain and physical function in its subscales in the treatment group were significantly lower than those in the control group (P<0.05). However, in the OFS+AI subgroup, there was no significant difference in stiffness between the treatment group and the control group (P>0.05) (Table 5).

[0140] Table 5 WOMAC score after 6 months of medication (n=108)

[0141]

[0142]

[0143] Note: *P<0.05, the difference is statistically significant.

[0144] After 6 months of medication, the treatment group and the control group were compared with the baseline, and the results showed that the WOMAC total score decreased significantly after medication (P<0.05). Subgroup analysis was performed using the endocrine treatment regimen as a stratification condition, and the results showed that in both subgroups of patients, the WOMAC total score decreased significantly after treatment (P<0.05), and the downward trend in the treatment group was more obvious than that in the control group ( Figure 2 ).

[0145] 1.2.3 TCM Syndrome Scoring

[0146] Among the 108 patients, there was no significant difference in the TCM symptom and sign scores between the pre-medication treatment group and the control group (P>0.05); subgroup analysis with endocrine treatment regimen as the stratification condition showed no significant difference (P>0.05), which was comparable (Table 6).

[0147] Table 6 TCM syndrome score before medication (n=108)

[0148]

[0149] After 3 months of medication, the scores of TCM symptoms and signs in the treatment group were lower than those in the control group, but the difference was not statistically significant (P>0.05) (Table 7).

[0150] Table 7 TCM syndrome scores after 3 months of medication (n=108)

[0151]

[0152] After 3 months of medication, the treatment group and the control group were compared within the group, and the results showed that the TCM symptom and sign scores were significantly reduced (P<0.05). Among them, the symptom and sign scores of the treatment group showed a more obvious downward trend. Subgroup analysis was performed using the endocrine treatment regimen as a stratification condition, and the results were similar to the overall results, with statistically significant differences (P<0.05) ( Figure 3 ).

[0153] After 6 months of medication, the TCM syndrome scores of the 108 patients in the treatment group were lower than those in the control group, and the difference was statistically significant (P<0.05) (Table 8).

[0154] Table 8 TCM syndrome scores after 6 months of medication (n=108)

[0155]

[0156] Note: *P<0.05, the difference is statistically significant.

[0157] After 6 months of medication, the treatment group and the control group were compared within the group, and the results showed that the TCM syndrome scores of both groups decreased significantly (P<0.05). Among them, the downward trend in the treatment group was more obvious. Subgroup analysis was performed using the endocrine treatment regimen as a stratification condition, and the results were similar to the overall trend. Figure 3 ).

[0158] 1.2.4 Bone density T value test

[0159] Among the 108 patients, there was no significant difference in bone mineral density T value (including lumbar vertebrae 1-4 and left femur) between the pre-treatment group and the control group (P>0.05); subgroup analysis with endocrine therapy regimen as the stratification condition showed no significant difference (P>0.05), which was comparable (Table 9).

[0160] Table 9 Bone density T value before medication (n = 108)

[0161]

[0162] After 6 months of medication, there was no significant difference in the bone density T values ​​of lumbar vertebrae 1-4 and left femur between the treatment group and the control group (P>0.05) (Table 10).

[0163] Table 10 Bone density T value after 6 months of medication (n = 108)

[0164]

[0165] After 6 months of medication, the treatment group and the control group were compared before and after medication. The results showed that the bone density T values ​​of lumbar vertebrae 1-4 and left femur in both groups still showed a downward trend after medication intervention, but the difference was not statistically significant (P>0.05). In terms of bone density of lumbar vertebrae and left femur, the T value of the treatment group decreased slightly slower.

[0166] Subgroup analysis was performed using endocrine therapy as a stratification condition. In terms of lumbar vertebrae 1-4 bone density in the AI ​​subgroup, the T value of the control group showed a small upward trend, but in terms of left femur bone density, the T value of the treatment group showed a small upward trend ( Figure 4 ).

[0167] 1.2.5 Three levels of bone metabolism

[0168] Among the 108 patients, there were no significant differences in the levels of three bone metabolism items (including total 25-hydroxyvitamin D3, osteocalcin, and β-collagen special sequence) between the pre-treatment group and the control group (P>0.05); subgroup analysis with endocrine therapy regimen as the stratification condition showed no significant differences (P>0.05), which was comparable (Table 11).

[0169] Table 11 Levels of three bone metabolism items before medication (n=108)

[0170]

[0171]

[0172] After 3 months of medication, there were no significant differences in the three levels of bone metabolism (including total 25-hydroxyvitamin D3, osteocalcin, and β-collagen special sequence) between the treatment group and the control group in the inter-group comparison (P>0.05) (Table 12); there were no significant differences in the bone metabolism levels between the two groups after medication in the intra-group comparison (P>0.05).

[0173] Subgroup analysis was performed using endocrine therapy as a stratification condition. The decrease trend of β-collagen special sequence in the AI+OFS subgroup treatment group was slightly slower than that in the control group, and the difference was not statistically significant (P>0.05) ( Figure 5 )

[0174] Table 12 Levels of three bone metabolism items after 3 months of medication (n=108)

[0175]

[0176] After 6 months of medication, there were no significant differences in the three levels of bone metabolism (including total 25-hydroxyvitamin D3, osteocalcin, and β-collagen special sequence) between the treatment group and the control group in the 108 patients (P>0.05) (Table 13).

[0177] Table 13 Levels of three bone metabolism items after 6 months of medication (n=108)

[0178]

[0179]

[0180] Intra-group comparison showed no significant differences in the levels of three bone metabolism between the treatment group and the control group before and after medication (P>0.05). Subgroup analysis was performed using endocrine therapy as a stratification condition. In osteocalcin, the AI ​​subgroup showed an upward trend, while the OFS+AI subgroup showed a downward trend (P>0.05). In β-collagen special sequence, the OFS+AI subgroup showed a downward trend, while the AI ​​subgroup showed an upward trend (P>0.05). Figure 5 ).

[0181] 1.2.6 Growth hormone

[0182] Among the 108 patients, there was no significant difference in growth hormone levels between the pre-treatment group and the control group (P>0.05); subgroup analysis using endocrine therapy regimen as a stratification condition showed no significant difference (P>0.05), which was comparable (Table 14).

[0183] Table 14 Growth hormone level before medication (n=108) [M (P25, P75)]

[0184]

[0185] After taking Chinese medicine for 3 months, the 108 patients had no significant difference in growth hormone levels between the treatment group and the control group (P>0.05) (Table 15); there was no significant difference in growth hormone levels between the two groups after medication (P>0.05). Subgroup analysis was performed using endocrine therapy as a stratification condition. The growth hormone level of the control group in the AI ​​subgroup increased significantly after 3 months of medication compared with that before medication (P<0.05) ( Figure 6 ).

[0186] Table 15 Growth hormone levels after 3 months of medication (n=108) [M (P25, P75)]

[0187]

[0188] After 6 months of medication, there was no significant difference in growth hormone levels between the treatment group and the control group in the inter-group comparison of 108 patients (P>0.05) (Table 16); there was no significant difference in growth hormone levels before and after medication between the two groups in the intra-group comparison (P>0.05); subgroup analysis was performed using endocrine therapy as a stratification condition, and there was no significant difference in the treatment group and the control group before and after medication 6 months in the two subgroups (P>0.05) ( Figure 6 ).

Claims

1. A Chinese medicine combination for treating breast cancer-related musculoskeletal diseases, characterized in that: The drug is prepared from the following raw materials in parts by weight: 12 parts of Cuscuta seeds, 30 parts of Rhizoma Cyperi, 15 parts of Eucommia bark, 9 parts of Fructus Corni, 15 parts of Fructus Lycii and 12 parts of processed Rhizoma Cyperi.

2. The Chinese medicine combination for treating breast cancer-related musculoskeletal diseases according to claim 1, characterized in that: The ingredients include 12g of Cuscuta seeds, 30g of Rhizoma Cyperi, 15g of Eucommia bark, 9g of Fructus Corni, 15g of Fructus Lycii and 12g of processed Cyperus rotundus.

3. A method for preparing a Chinese medicine combination, comprising the Chinese medicine combination for treating breast cancer-related musculoskeletal diseases as claimed in claim 2, characterized in that: Prepare the prescribed amount of Cuscuta australis, Achyranthes bidentata, Eucommia ulmoides, Cornus officinalis, Lycium barbarum and processed Cyperus rotundus, add 1000 ml of purified water, simmer for 40 minutes, and filter out the medicinal liquid.

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