Efficacy and safety of the Bushen Tiaochong recipe combined with alendronate sodium for the treatment of postmenopausal senile degenerative osteoporosis: study protocol and preliminary results of a randomized controlled trial

Mei-ge Qi, Lin Qi, Li Li, Jing Song

Department of Gynecologic Oncology, Affiliated Hospital of Qinghai University, Xining, Qinghai Province, China

INTRODUCTION

Background

Osteoporosis is a systemic bone disease characterized by low bone mass, damage to bone microstructures, increased bone fragility, and brittle fracture.1-4Postmenopausal senile degenerative osteoporosis usually occurs in women 5–10 years after menopause, and is mainly related to the lack of estrogen after menopause.5-7Alendronate sodium is commonly used to treat osteoporosis, but when used alone for postmenopausal elderly patients with degenerative osteoporosis, it has a moderate effect and many adverse reactions.7-11

Chinese scholars believe that the pathogenesis of postmenopausal senile degenerative osteoporosis is mainly due to a de ficiency of “kidney essence,” which is also strongly associated with spleen and stomach weakness, liver-blood de ficiency, and blood stasis.12The Bushen Tiaochong recipe from traditional Chinese medicine can warm the kidneys,nourish both yin and blood, strengthen muscles and bones,activate blood circulation, and dissipate blood stasis. Icariin,the main active ingredient in the flowering plant Epimedium and a major component of the recipe, is a phytoestrogen and has an estrogen-like effect. It can prevent against bone loss and improve bone strength, and has a de finite effect on the treatment of postmenopausal senile degenerative osteoporosis.13,14

Main objective

The objective of this study is to determine the ef ficacy and safety of the Bushen Tiaochong recipe combined with alendronate sodium in the treatment of postmenopausal senile degenerative osteoporosis.

METHODS/DESIGN

Study design

This prospective, randomized, controlled trial will analyze the data from 200 patients with postmenopausal senile degenerative osteoporosis. These patients will be randomly divided into two groups. In the control group, patients will be given alendronate sodium tablets 10 mg/d and calcium carbonate D3 chewable tablets 0.6 g/d. The observation group will receive the same treatment with the addition of the Bushen Tiaochong recipe, simmering, twice per day (once in the morning and once in the evening). The course of treatment will be 6 months in both groups. We will measure the total ef ficacy 6 months after treatment, as well as Visual Analogue Scale scores for waist and back pain, L2–4bone mineral density, serological indicators,and the incidence of adverse reactions 6 months after the start of treatment. Figure 1 shows the flow chart of the study protocol.

Strengths and limitations

· Combination of Chinese and Western medicine in the treatment of postmenopausal senile degenerative osteoporosis is of great current interest.

· Relatively small sample size.

· Short follow-up time.

Figure 1: Flow chart of the trial protocol.

Study setting

Af filiated Hospital of Qinghai University, Qinghai Province, China.

Study population

Two hundred female patients of Han ethnicity, aged 55 to 70 years, with postmenopausal senile degenerative osteoporosis, will be enrolled from the out-patient clinic of the Af filiated Hospital of Qinghai University, China.

Inclusion criteria

Patients who meet all of the following criteria will be con-sidered for study inclusion:

· Diagnosed in accordance with the Guidelines for the diagnosis and treatment of primary osteoporosis (2011)15

· Kidney deficiency and blood stasis syndrome in accordance with “Guiding principles of clinical study of new Chinese medicine”16

· Two years of natural menopause

· Provision of signed informed consent

Exclusion criteria

Patients who meet one or more of the following conditions will be excluded from the study:

· Metabolic bone diseases, such as hyperthyroidism,diabetes, and chronic kidney disease

· Sex hormone replacement therapy in previous 3 months

· Severe heart, cerebrovascular, liver, kidney, or hematopoietic system diseases

·Mental illness

· Tumor disease

· Bone fracture

· Abnormal uterine bleeding

Withdrawal criteria

Patients who meet one or more of the following criteria during the trial will be withdrawn from the study:

· Not compliant with drug treatment

· Failure to complete the follow-up

Recruitment

We will recruit 200 out-patients with postmenopausal senile degenerative osteoporosis from the Af filiated Hospital of Qinghai University of China from January to December 2018. Lea flets that contain the details of the study will be sent to patients with senile degenerative osteoporosis in our clinic. Patients who are interested in participating in the study can directly call the study leader. After screening,based on the inclusion and exclusion criteria and provision of informed consent, these patients will be enrolled in our study and data will be obtained from these patients.

Randomization and blinding

The patients will be assigned numbers from 1 to 200. A random number table will be created using SPSS 13.0 software (SPSS, Chicago, IL, USA). The 200 numbers will be randomized into the two study groups. This is an open-label trial, so no blinding method will be used.

Interventions

In the control group, patients will be given alendronate sodium tablets (GYZZ H20061303; Ouyi Pharmaceutical Co., Ltd., China Shijiazhuang Pharmaceutical Group,Shijiazhuang, China) 10 mg/d with 200 mL warm water in the morning before having breakfast. At least 30 minutes later, the patients can eat. The patients will then be given calcium carbonate D3 chewable tablets (GYZZ H10950030; Wyeth Pharmaceutical Co., Ltd., Suzhou,China) 0.6 g/d.

In the observation group, patients will be given the Bushen Tiaochong recipe17, which mainly contains Epimedium brevicornu Maxim 10 g, Fructus Psoraleae 10 g, Rhizoma Curculiginis 10 g, Colla Cornus Cervi 10 g, Radix Rehmanniae preparata 20 g, Fructus Lycii 20 g, Herba Ecliptae 20 g, Herba Taxilli 15 g, Radix Dipsaci 15 g, Cortex Eucommiae 15 g, Concha Ostreae 30 g, Radix Salviae Miltiorrhiae 15 g, Radix Cyathulae 15 g, Flos Carthami 6 g, and Rhizoma Drynariae 10 g, simmering, twice per day(once in the morning and once in the evening). The course of treatment will be 6 months in both groups.

Efficacy evaluation

Primary outcome measure

Total ef ficacy will be assessed 6 months after treatment: In accordance with the “Guiding principles of clinical study of new Chinese medicine”,16ef ficacy standards are as follows:markedly effective = pain completely disappears, increased bone mineral density; effective = pain is obviously relieved,or no decrease in bone mineral density; and ineffective = no improvement in any aspects compared with pre-treatment.Total ef ficacy is equal to [(number of cases of markedly effective + number of cases of effective effect)/number of cases of ineffective] × 100%.

Secondary outcome measures

· Visual Analogue Scale scores for waist and back pain will be assessed before and 6 months after treatment. Scores range from 0 to 10, with a higher score representing more severe pain.18

· L2–4bone mineral density will be assessed before and 6 months after treatment using a dual energy X-ray bone density meter (TEDA Shenghong Medical Apparatus Co., Ltd.,Tianjin, China) to determine the improvement in bone mass.· Serological indicators will be assessed before and 6 months after treatment using a blood biochemical analyzer(Guangzhou Lebang Medical Equipment Co., Ltd., Guangzhou, China) to measure serum levels of calcium, phosphorus, alkaline phosphatase, and osteocalcin. An immunoradiometric assay will be performed to detect estradiol,follicle stimulating hormone, and luteinizing hormone. An enzyme-linked immunosorbent assay kit (Shanghai Nanke Biotechnology, Shanghai, China) will be used to determine interleukin-1 and interleukin-6 levels.

· The incidence of adverse reactions 6 months after treat-ment will be evaluated. The incidence of adverse reactions is equal to the number of patients with adverse reactions/the total number of patients × 100%.

The schedule of outcome measurement assessments is shown in Table 1.

Safety evaluations

Adverse reactions, including fracture, infection, dizziness,headache, nausea, and vomiting associated with the study treatment, will be directly recorded. Adverse reactions, the reasons for adverse reactions and explanations will be listed.If severe adverse reactions occur, such as coma, shock, or bleeding, these will be reported to the hospital ethics committee and the test and supervision department.

Audits

Inital stage

The protocols have been approved by the Ethics Committee of the Af filiated Hospital of Qinghai University of China.We will sign the trial agreement with the hospital.

During the trial

Regular monitoring ensures that the enrolled patients will comply with the inclusion criteria and be excluded if they meet exclusion criteria. All procedures will be in strict accordance with the scheme to ensure data integrity.

Final stage

After the patient completes all examinations, a final followup visit will be required to con firm the correctness of the previous follow-up data.

Statistical analysis

Statistical design, methods, and analysis principle

All data will be analyzed using SPSS 13.0 software (SPSS,Chicago, IL, USA), according to the intention-to-treat principle. Normally distributed measurement data will be expressed as the mean ± standard deviation. Non-normally distributed measurement data will be expressed as the lower quartile (q1) and median and upper quartiles (q3). Numerical data will be presented as percentages.

The total ef ficacy and incidence of adverse reactions will be compared using a Pearson's chi-square test between the two groups. Visual Analogue Scale scores for waist and back pain, bone mineral density results, and serological indicators will be compared using two sample t-test analyses between the two groups. The above-mentioned indicators will be compared using a paired t-test before and after treatment in the two groups. The signi ficance level will be α = 0.05.

Sample size

In accordance with our experience17, we hypothesize that the total ef ficacy at 6 months after treatment will be 90% in the observation group and 75% in the control group. Taking β = 0.2 and power = 80% with a signi ficance level of α =0.05, the final effective sample size of n = 97 per group will be calculated using PASS 11.0 software (PASS, Kaysville,UT, USA). If we assume a patient loss rate of 20%, we will require n = 117 patients per group. After screening according to the inclusion and exclusion criteria, we will include n = 100 patients per group.

Data missing processing

In the case of missing data, the patient will be excluded from the study and subsequently replaced with a new participant.

Baseline data collection

The baseline information that will be collected, including demographic data, general disease history, and clinical data,is shown in Table 2.

Data management

The whole trial process will strictly adhere to the quality management standards for clinical trials. Case report forms will be recorded completely, accurately, clearly, and objectively. All data will be input into the computer, locked, and stored. To ensure the accuracy of the data, two data entrypersonnel will perform double entry and proofreading,separately. After checking, the database will be locked by a data manager, and will not be altered.

Table 2: Baseline data and general disease history of the included patients

Ethical requirements and informed consent

The study protocol will be conducted in accordance with the Declaration of Helsinki. The data will be reported in accordance with the Standard Protocol Items:Recommendations for Interventional Trials (SPIRIT)(Additional file 1). Researchers are responsible for providing trial protocols, informed consent, and information provided to the subjects so as to get the independent approval document for the implementation of the clinical research. The trial can be carried out only after obtaining the approval of the ethics committee. This trial has been approved by the Ethics Committee of the Af filiated Hospital of Qinghai University of China (approval number: QHY1703F).

PRELIMINARY RESULTS

The results of a preliminary experiment including 124 patients with postmenopausal senile degenerative osteoporosis who received the same treatment as in the present study have been obtained as follows.

At 6 months after treatment, the total ef ficacy, L2–4bone mineral density, serum levels of calcium and estradiol were higher in the observation group than in the control group(P ＜ 0.05). Visual Analogue Scale scores, serum levels of alkaline phosphatase, osteocalcin, interleukin-1, and interleukin-6 were lower in the observation group than in the control group (P ＜ 0.05). Follicle stimulating hormone levels were not signi ficantly different between the two groups after treatment (P ＞ 0.05).19

DISCUSSION

Significance of this study

The treatment of osteoporosis with traditional Chinese medicine is becoming a research area of great interest.The Bushen Tiaochong recipe combined with alendronate sodium can make up for the shortcomings of the traditional Chinese medicine prescription and also for the adverse effects associated with the use of alendronate sodium alone,and achieve the purpose of early analgesia with a prolonged therapeutic effect. It is worthwhile to explore possible clinical promotion in the future.

Limitations of this study

This trial will not be blinded method or have a placebo control. The sample size is relatively small. The reliability of the results of this randomized controlled trial will be affected, and we will redesign more rigorous randomized controlled trials in future research.20,21

Evidence for contribution to future studies

The aim of the trial is to prove that the Bushen Tiaochong recipe combined with alendronate sodium can relieve low back pain, increase L2–4bone mineral density, increase serum calcium levels, and reduce osteocalcin and alkaline phosphatase levels in patients with menopausal osteoporosis. The combined effect is expected to be better than that of either treatment alone.

Author contributions

Study conception and design, manuscript writing and proofreading: MGQ. Constructive revisions: LQ. Assistance of experiment implementation: LL and JS. All authors approved the final version of the manuscript.

Conflicts of interest

None declared.

Research ethics

This trial has been approved by the Ethics Committee of Af filiated Hospital of Qinghai University of China (approval number:QHY1703F). The study will be performed in accordance with theDeclaration of Helsinkiand relevant ethical principles.

Declaration of patient consent

The authors certify that they will obtain patient consent forms. In the form, patients will give their consent for their images and other clinical information to be reported in the journal. The patients will understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Data sharing statement

Datasets analyzed during the current study are available from the corresponding author on reasonable request.

Plagiarism check

Checked twice by iThenticate.

Peer review

Externally peer reviewed.

Open access statement

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under identical terms.

Additional file

Additional flie 1: SPIRIT checklist.

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