# The Efficacy and Safety of Traditional Chinese Medicine Tonifying-Shen (Kidney) Principle for Primary Osteoporosis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Authors: Junquan Liang; Fengyi Wang; Jiajia Huang; Yunxiang Xu; Guizhen Chen
Journal: Evidence-Based Complementary and Alternative Medicine
 (2020)

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## Abstract

Objective. This study aimed to appraise the efficacy and safety of the tonifying-Shen (kidney) principle (TS (TK) principle) for primary osteoporosis (POP). Methods. Randomized controlled clinical trials (RCTs) using the TS (TK) principle for POP were searched from eight electronic databases to search for relevant literature that was published from the initiation to September 2019. Two reviewers performed study selection, data extraction, data synthesis, and quality assessment independently. Review Manager 5.3 software was used to assess the risk of bias and conduct the data synthesis. We assessed the quality of evidence for outcomes by using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Results. Thirty-six studies with 3617 participants were included. Meta-analysis showed a consistently superior effect of the TS (TK) principle combined with conventional Western medicine (CWM) in terms of total effectiveness rates (RR = 1.28; 95% CI (1.23, 1.33); P<0.00001), BMD of the lumbar spine (SMD = 0.71; 95% CI (0.47, 0.95); P<0.00001) and proximal femur (SMD = 0.94; 95% CI (0.49, 1.38); P<0.00001), TCM symptom integral (SMD = −1.23; 95% CI (−1.43, −1.02); P<0.00001), and VAS scores (SMD = −3.88; 95% CI (−5.29, −2.46); P<0.00001), when compared to using CWM alone and with significant differences. Besides, in respect of adverse effects, it showed no significant statistical difference between the experimental and control groups, RR = 0.99 and 95% CI (0.65, 1.51), P=0.97. Conclusion. Our meta-analysis provides promising evidence to suggest that using the TS (TK) principle combined with CWM for POP is more effective than using CWM alone. Also, both of them are safe and reliable for POP.


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## Body

## 1. Introduction

Primary osteoporosis (POP), also called “a silent disease,” is one of the pandemic public health issues that seriously threaten people’s health all over the world [1]. Theoretically, POP and secondary osteoporosis belong to the field of osteoporosis (OP). POP includes two major types: postmenopausal osteoporosis (PMOP) and age-related or senile osteoporosis [2]. POP is characterized by decreased bone mass and degenerated bone microstructure, which contributes to a high risk of bone fragility and fracture [3, 4]. It is estimated that the number of individuals aged 50 years or over at high risk of osteoporotic fracture worldwide was at 158 million in 2010 and is set to double by 2040 [5]. In China, because of the largest population and the increasing proportion of elderly people, osteoporosis has become a severe challenge to the Chinese family, society, and government [6, 7]. Therefore, an effective prevention and treatment method is urgently needed for POP. Management of POP includes nonpharmacologic treatment and pharmacologic treatment. Conventional Western medicines (CWM) including antiresorptive or anabolic are widely used in the treatment of POP [8–10]. However, due to adverse effects and risk of cancer, the use of CWM as long-term treatment is limited [11].It is well documented that traditional Chinese medicine (TCM) is commonly combined with pharmacotherapy for POP in China [12–14]. In the theory of TCM, there is no particular disease named POP. According to the clinical symptoms, POP belongs to the TCM category of “Guwei (flaccidity of bones),” “Guku (dryness of bones),” “Guji (disease of bones),” “Gukong (depletion of bones), and Gubi (impediment of bones)” [15]. “Shen (kidney) dominating the bone” is the most fundamental theory in TCM. Shen essence (kidney essence) is closely related to bone physiology and pathology. The sufficient Shen essence can keep the bone healthy and strong. On the contrary, the deficiency of Shen essence will lead to a series of bone-related symptoms. Besides, “liver controlling tendon,” is involved in bone health. Also, the spleen and stomach are considered as the postnatal foundations of organisms and are the material sources of bone growth. Therefore, the tonifying-Shen (kidney) principle (TS (TK) principle) mainly includes bushen huoxue, bushen zhuanggu, bushen jianpi, and buyi ganshen, which are widely used in combination with other TCM therapies or CWM for the treatment of POP. And, this significant principle has its essential meaning in curing POP [16].In recent years, numerous meta-analyses were carried out to investigate the efficacy of acupuncture or Chinese herbal medicine for POP [17]. However, there was still no sufficient evidence to draw definitive conclusions as most studies were not comparative analysis aiming at the effect of the TS (TK) principle for POP. Besides, most of the meta-analyses did not explore the safety of particular interventions. Therefore, the purpose of this study was to systematically identify available randomized clinical trials (RCTs) using the TS (TK) principle combined with CWM for POP to appraise its efficacy and safety.


## 2. Materials and Methods

### 2.1. Study Registration

The study has been registered in PROSPERO (registration number: CRD42020151768). The review reporting was conducted in compliance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement guidelines.


### 2.2. Study Design

#### 2.2.1. Inclusion Criteria

(1) Types of Participants and Interventions. All RCTs that were reporting the application of the TS (TK) principle combined with CWM for POP were included. The interventions of these studies must include the TS (TK) principle in the experimental group. Studies must be published in English or Chinese language. TS (TK) principle mainly includes bushen huoxue, bushen zhuanggu, bushen jianpi, and buyi ganshen. Specific treatment methods include traditional Chinese herbal medicine, acupuncture and moxibustion combined with traditional Chinese herbal medicine, acupoint catgut embedding, and acupoint injection. POP patients were included. There is no restriction on gender, race, ethnicity, or nation. Patients in the treatment group were given the TS (TK) principle combined with CWM, while patients in the control group were given CWM alone. The dosages and courses were not limited in our studies.(2) Types of Outcome Measures. The primary outcomes included effectiveness rate and bone mineral density (BMD) of the lumbar spine and proximal femur (femoral neck or total hip). The secondary outcomes consisted of VAS scores and TCM symptom integral. Besides, adverse events were also assessed as a safety measurement.


#### 2.2.2. Exclusion Criteria

Studies with the following characteristics were excluded: irrelevant to TS (TK) principle studies; studies without consistent diagnostic criteria or relevant outcome indicators; non-English or Chinese-language articles; duplicate reports or the data cannot be extracted; case reports, animal experiences, qualitative studies, comments, or review articles.


### 2.3. Literature Search Strategy

We searched four international electronic databases (PubMed, Cochrane Library, EMBASE, and Web of Science) and four Chinese electronic databases (CNKI, VIP, Wanfang, and CBM) from their initiation to September 2019 to collect for relevant literature. The literature search was constructed around search terms for TS (TK) principle, POP, and randomized controlled trials and adapted for each database as necessary. The references of the included studies were also screened for further material for inclusion. The detailed search strategy for PubMed is in Table1. Search strategies were also used for other electronic databases.Table 1
The search strategy used in the PubMed database.
Serial numberSearch items#1Bushen#2Tonifying Shen#3Bu Shen#4Yishen#5Nourishing the kidney#6Tonifying the kidney#7Yi Shen#8Tonifying kidney#9Nourishing kidney#10Nourishing Shen#11Reinforcing the kidney#12Reinforcing kidney#13Reinforcing Shen#14Invigorating the kidney#15Invigorating kidney#16Invigorating Shen#17Kidney-reinforcing#18Kidney reinforcing#19Shen reinforcing#20Shen-reinforcing#21Kidney-invigorating#22Kidney invigorating#23Shen-invigorating#24Kidney-tonifying#25Shen-tonifying#26Kidney tonifying#27Shen tonifying#28Shen invigorating#29Invigorating Shen#30#1 or #2—#29#31Primary osteoporosis#32Osteoporosis#33Age-related osteoporosis#34Age-related osteoporosis#35Osteoporosis, senile#36Osteoporosis, involutional#37Senile osteoporosis#38Osteoporosis, age-related#39Osteoporosis, age-related#40Bone loss, age-related#41Age-related bone loss#42Age-related bone losses#43Bone loss, age-related#44Bone losses, age-related#45#31 or #32—#44#46Randomized controlled trials#47Randomized#48Randomly#49Random#50RCTs#51#46 or #47—#50#52#30 and #45 and #51


### 2.4. Study Selection and Data Extraction

As a first step in the data handling process, titles and abstracts of all studies retrieved by the search strategies were screened for relevance, and all those that were clearly irrelevant have been discarded.As a second step, two review team members (Junquan Liang and Fengyi Wang) independently assessed the eligibility of the studies by using the predefined inclusion and exclusion criteria. Besides, for the studies that meet the inclusion criteria, the whole article was read by reviewers to ensure that the entire study met the criteria and was prepared to extract relevant information. The disagreements on whether including a specific study or not were resolved by discussion between the reviewers. The lacking information was requested by contacting the writer of the original article.The information extracted by the two independent review team members included the following: study setting, population study, participant demographics and baseline characteristics, details of the intervention and control conditions, study methodology, outcomes and treatment periods, information for the assessment of the risk of bias. The discrepancies were identified and resolved through discussion (with a third author where necessary). Missing data were requested from the study authors.


### 2.5. Risk of Bias Assessment

There were two reviewers involved in the quality assessment process, and any major disagreements were resolved by discussion to define the final set of included studies.Two independent reviewers assessed the risk of bias by considering the following characteristics: randomization sequence generation, treatment allocation concealment, blinding method, completeness of outcome data, selective outcome reporting, and other sources of bias. Besides, the Cochrane Collaboration’s risk of bias assessment tool was used to assess the quality of the individual included studies.


### 2.6. Data Synthesis

Review Manager 5.3 software was used to carry out the quantitative synthesis. Mean difference (MD) or standardized mean difference (SMD) was used for continuous data. Risk ratio (RR) was used for the analysis of dichotomous data. Both were given a 95% confidence interval (CI). In the case of homogeneous data (I2 ≤ 50%, P>0.10), the fixed-effect model was adopted for the meta-analysis. Otherwise, the sources of heterogeneity were further analyzed. After excluding the influence of marked clinical heterogeneity, a random-effect model was adopted to perform the meta-analysis. Sensitivity and bias risk analyses were also performed.


#### 2.6.1. Analysis of Subgroups

We performed some planned subgroup analysis: different specific therapies (bushen huoxue, bushen zhuanggu, bushen jianpi, and buyi ganshen) included in the TS (TK) principle, different kinds of treatment methods (traditional Chinese herbal medicine, acupuncture and moxibustion combined with traditional Chinese herbal medicine, acupoint catgut embedding, and acupoint injection), different parts of BMD examination (lumbar spine and proximal femur (femoral neck or total hip)), and different treatment periods of the TS (TK) principle (≤3 months, 3–6 months, and >6 months).


#### 2.6.2. Sensitivity Analysis and Reporting Bias Analysis

Sensitivity analysis was carried out to identify the robustness and stability of pooled outcome results by removing the low-quality studies. We have performed a funnel plot of the primary outcome (effectiveness rates of different treatment methods included in the tonifying-Shen (kidney) principle) to evaluate the reporting bias.


### 2.7. Quality of Evidence

We assessed the quality of evidence for outcomes by using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system [18].


## 2.1. Study Registration

The study has been registered in PROSPERO (registration number: CRD42020151768). The review reporting was conducted in compliance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement guidelines.


## 2.2. Study Design

### 2.2.1. Inclusion Criteria

(1) Types of Participants and Interventions. All RCTs that were reporting the application of the TS (TK) principle combined with CWM for POP were included. The interventions of these studies must include the TS (TK) principle in the experimental group. Studies must be published in English or Chinese language. TS (TK) principle mainly includes bushen huoxue, bushen zhuanggu, bushen jianpi, and buyi ganshen. Specific treatment methods include traditional Chinese herbal medicine, acupuncture and moxibustion combined with traditional Chinese herbal medicine, acupoint catgut embedding, and acupoint injection. POP patients were included. There is no restriction on gender, race, ethnicity, or nation. Patients in the treatment group were given the TS (TK) principle combined with CWM, while patients in the control group were given CWM alone. The dosages and courses were not limited in our studies.(2) Types of Outcome Measures. The primary outcomes included effectiveness rate and bone mineral density (BMD) of the lumbar spine and proximal femur (femoral neck or total hip). The secondary outcomes consisted of VAS scores and TCM symptom integral. Besides, adverse events were also assessed as a safety measurement.


### 2.2.2. Exclusion Criteria

Studies with the following characteristics were excluded: irrelevant to TS (TK) principle studies; studies without consistent diagnostic criteria or relevant outcome indicators; non-English or Chinese-language articles; duplicate reports or the data cannot be extracted; case reports, animal experiences, qualitative studies, comments, or review articles.


## 2.2.1. Inclusion Criteria

(1) Types of Participants and Interventions. All RCTs that were reporting the application of the TS (TK) principle combined with CWM for POP were included. The interventions of these studies must include the TS (TK) principle in the experimental group. Studies must be published in English or Chinese language. TS (TK) principle mainly includes bushen huoxue, bushen zhuanggu, bushen jianpi, and buyi ganshen. Specific treatment methods include traditional Chinese herbal medicine, acupuncture and moxibustion combined with traditional Chinese herbal medicine, acupoint catgut embedding, and acupoint injection. POP patients were included. There is no restriction on gender, race, ethnicity, or nation. Patients in the treatment group were given the TS (TK) principle combined with CWM, while patients in the control group were given CWM alone. The dosages and courses were not limited in our studies.(2) Types of Outcome Measures. The primary outcomes included effectiveness rate and bone mineral density (BMD) of the lumbar spine and proximal femur (femoral neck or total hip). The secondary outcomes consisted of VAS scores and TCM symptom integral. Besides, adverse events were also assessed as a safety measurement.


## 2.2.2. Exclusion Criteria

Studies with the following characteristics were excluded: irrelevant to TS (TK) principle studies; studies without consistent diagnostic criteria or relevant outcome indicators; non-English or Chinese-language articles; duplicate reports or the data cannot be extracted; case reports, animal experiences, qualitative studies, comments, or review articles.


## 2.3. Literature Search Strategy

We searched four international electronic databases (PubMed, Cochrane Library, EMBASE, and Web of Science) and four Chinese electronic databases (CNKI, VIP, Wanfang, and CBM) from their initiation to September 2019 to collect for relevant literature. The literature search was constructed around search terms for TS (TK) principle, POP, and randomized controlled trials and adapted for each database as necessary. The references of the included studies were also screened for further material for inclusion. The detailed search strategy for PubMed is in Table1. Search strategies were also used for other electronic databases.Table 1
The search strategy used in the PubMed database.
Serial numberSearch items#1Bushen#2Tonifying Shen#3Bu Shen#4Yishen#5Nourishing the kidney#6Tonifying the kidney#7Yi Shen#8Tonifying kidney#9Nourishing kidney#10Nourishing Shen#11Reinforcing the kidney#12Reinforcing kidney#13Reinforcing Shen#14Invigorating the kidney#15Invigorating kidney#16Invigorating Shen#17Kidney-reinforcing#18Kidney reinforcing#19Shen reinforcing#20Shen-reinforcing#21Kidney-invigorating#22Kidney invigorating#23Shen-invigorating#24Kidney-tonifying#25Shen-tonifying#26Kidney tonifying#27Shen tonifying#28Shen invigorating#29Invigorating Shen#30#1 or #2—#29#31Primary osteoporosis#32Osteoporosis#33Age-related osteoporosis#34Age-related osteoporosis#35Osteoporosis, senile#36Osteoporosis, involutional#37Senile osteoporosis#38Osteoporosis, age-related#39Osteoporosis, age-related#40Bone loss, age-related#41Age-related bone loss#42Age-related bone losses#43Bone loss, age-related#44Bone losses, age-related#45#31 or #32—#44#46Randomized controlled trials#47Randomized#48Randomly#49Random#50RCTs#51#46 or #47—#50#52#30 and #45 and #51


## 2.4. Study Selection and Data Extraction

As a first step in the data handling process, titles and abstracts of all studies retrieved by the search strategies were screened for relevance, and all those that were clearly irrelevant have been discarded.As a second step, two review team members (Junquan Liang and Fengyi Wang) independently assessed the eligibility of the studies by using the predefined inclusion and exclusion criteria. Besides, for the studies that meet the inclusion criteria, the whole article was read by reviewers to ensure that the entire study met the criteria and was prepared to extract relevant information. The disagreements on whether including a specific study or not were resolved by discussion between the reviewers. The lacking information was requested by contacting the writer of the original article.The information extracted by the two independent review team members included the following: study setting, population study, participant demographics and baseline characteristics, details of the intervention and control conditions, study methodology, outcomes and treatment periods, information for the assessment of the risk of bias. The discrepancies were identified and resolved through discussion (with a third author where necessary). Missing data were requested from the study authors.


## 2.5. Risk of Bias Assessment

There were two reviewers involved in the quality assessment process, and any major disagreements were resolved by discussion to define the final set of included studies.Two independent reviewers assessed the risk of bias by considering the following characteristics: randomization sequence generation, treatment allocation concealment, blinding method, completeness of outcome data, selective outcome reporting, and other sources of bias. Besides, the Cochrane Collaboration’s risk of bias assessment tool was used to assess the quality of the individual included studies.


## 2.6. Data Synthesis

Review Manager 5.3 software was used to carry out the quantitative synthesis. Mean difference (MD) or standardized mean difference (SMD) was used for continuous data. Risk ratio (RR) was used for the analysis of dichotomous data. Both were given a 95% confidence interval (CI). In the case of homogeneous data (I2 ≤ 50%, P>0.10), the fixed-effect model was adopted for the meta-analysis. Otherwise, the sources of heterogeneity were further analyzed. After excluding the influence of marked clinical heterogeneity, a random-effect model was adopted to perform the meta-analysis. Sensitivity and bias risk analyses were also performed.


### 2.6.1. Analysis of Subgroups

We performed some planned subgroup analysis: different specific therapies (bushen huoxue, bushen zhuanggu, bushen jianpi, and buyi ganshen) included in the TS (TK) principle, different kinds of treatment methods (traditional Chinese herbal medicine, acupuncture and moxibustion combined with traditional Chinese herbal medicine, acupoint catgut embedding, and acupoint injection), different parts of BMD examination (lumbar spine and proximal femur (femoral neck or total hip)), and different treatment periods of the TS (TK) principle (≤3 months, 3–6 months, and >6 months).


### 2.6.2. Sensitivity Analysis and Reporting Bias Analysis

Sensitivity analysis was carried out to identify the robustness and stability of pooled outcome results by removing the low-quality studies. We have performed a funnel plot of the primary outcome (effectiveness rates of different treatment methods included in the tonifying-Shen (kidney) principle) to evaluate the reporting bias.


## 2.6.1. Analysis of Subgroups

We performed some planned subgroup analysis: different specific therapies (bushen huoxue, bushen zhuanggu, bushen jianpi, and buyi ganshen) included in the TS (TK) principle, different kinds of treatment methods (traditional Chinese herbal medicine, acupuncture and moxibustion combined with traditional Chinese herbal medicine, acupoint catgut embedding, and acupoint injection), different parts of BMD examination (lumbar spine and proximal femur (femoral neck or total hip)), and different treatment periods of the TS (TK) principle (≤3 months, 3–6 months, and >6 months).


## 2.6.2. Sensitivity Analysis and Reporting Bias Analysis

Sensitivity analysis was carried out to identify the robustness and stability of pooled outcome results by removing the low-quality studies. We have performed a funnel plot of the primary outcome (effectiveness rates of different treatment methods included in the tonifying-Shen (kidney) principle) to evaluate the reporting bias.


## 2.7. Quality of Evidence

We assessed the quality of evidence for outcomes by using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system [18].


## 3. Results

### 3.1. Study Description and Participants

We obtained 390 relevant studies through preliminary searches. After multiple filtering steps, 36 RCTs with a total of 3617 participants were ultimately included in this systematic review. The flowchart of all study selection procedures is shown in Figure1.Figure 1
The flowchart of the selection procedure.The 36 included studies involved 3617 participants. Among these studies, apart from combined with CWM, 23 studies reported using TCM herbal medicine [19–41], 5 studies reported using acupuncture and moxibustion combined with traditional Chinese herbal medicine [42–46], 9 studies reported using acupoint catgut embedding [25, 26, 40, 47–52], and 2 studies reported using acupoint injection [53, 54]. Besides, 3 studies divided their experimental group into two groups, respectively (acupoint catgut embedding group and TCM herbal medicine group) [25, 26, 40]. The detailed characteristics of the included studies are shown in Table 2.Table 2
Characteristics of the included studies.
No.Included studies (author, year)Age (years)Participants (experimental group/control group)InterventionOutcomesAdverse effects (experimental group/control)Treatment periods (months)Follow-up (months)Control groupExperimental groupControl groupExperimental groupSecondary outcomesPrimary outcomes1Zheng et al. [19], 201963.9 ± 2.8163.91 ± 2.8670/70Placebo capsules ± calcium carbonateBushen Yijing Fang ± calcium carbonate—BMD of femoral neck; adverse effects9/8361202Liu and Wang [42], 201656.15 ± 6.7755.86 ± 6.9262/62Alendronate sodium tablets ± calcium carbonate D3 tabletsErxian Bushen decoction ± acupuncture and moxibustion ± alendronate sodium tablets ± calcium carbonate D3 tablets—Effectiveness rate; BMD of femoral neck and lumbar spine—6—3Xu et al. [43], 201863.90 ± 7.5965.16 ± 6.8232/31Calcium carbonate D3Thunder-fire moxibustion ± calcium carbonate D3VAS scores——114Zhu et al. [20], 201264.9 ± 6.065.4 ± 6.361/61Calcium carbonate ± vitamin DXian Ling Gu Bao capsules ± calcium carbonate ± vitamin D—BMD of femoral neck and lumbar spine; adverse effects11/1112125Zhao and Yan [21], 201861.3 ± 4.162.1 ± 4.150/50Caltrate ± alpha D3 calciferolTraditional Chinese medicine prescription ± caltrate ± alpha D3 calciferolVAS scoresEffectiveness rate; BMD of lumbar spine (L2–4); adverse effects9/6666Yuan et al. [22], 2014——40/40Alendronate ± calcium carbonate D3Chinese herbal medicine ± alendronate ± calcium carbonate D3—Effectiveness rate—6—7Huang [23], 201565.5 ± 1.665.7 ± 1.570/70Calcium carbonate D3 ± alfacalcidol soft capsulesBushenhuoxuetang ± calcium carbonate D3 ± alfacalcidol soft capsulesVAS scoresEffectiveness rate—2—8Wu et al. [24], 200556.4 ± 4.655.6 ± 4.334/34Caltrate D600Xian Ling Gu Bao capsules ± caltrate D600—BMD of femoral neck and lumbar spine—12—9Liu et al. [25], 2011 (3)62.8 ± 5.9Liu 2011 (3)∗: 63.7 ± 3.8; Liu 2011 (3): 61.8 ± 8.3A: 35/35; B: 35Calcichew D3 tabletsLiu 2011 (3)∗: acupoint catgut embedding ± calcichew D3 tablets; Liu 2011 (3): Xianling Gubao capsules ± calcichew D3 tabletsVAS scoresEffectiveness rate; BMD of lumbar spine—6—10Lu [47], 201462.14 ± 6.3460.84 ± 6.9525/22Calcium carbonate D3Acupoint catgut embedding ± calcium carbonate D3—Effectiveness rate—6—11Han et al. [44], 201167.39 ± 4. 0567.42 ± 3. 8930/30CaltrateShuganwenshentanyushuangjietang ± acupuncture and moxibustion ± caltrate—Effectiveness rate—6—12Liu et al. [26], 2011 (1)62.8 ± 5.9Liu 2011 (1)∗: 63.7 ± 3.8; Liu 2011 (1): 61.8 ± 8.3A: 35/35 B: 35Calcichew D3 tabletsLiu 2011 (1)∗: acupoint catgut embedding ± calcichew D3 tablets; Liu 2011 (1): Xian Ling Gu Bao capsules ± calcichew D3 tabletsTCM symptom integral—0/0/46—13Peng et al. [48], 2017——35/35Calcichew D3 tablets ± alendronate sodium tabletsAcupoint catgut embedding ± calcichew D3 tablets ± alendronate sodium tabletsVAS scoresEffectiveness rate; BMD of lumbar spine—3—14Peng et al. [49], 2018——45/45Calcichew D3 tablets ± alendronate sodium tabletsAcupoint catgut embedding ± calcichew D3 tablets ± alendronate sodium tabletsVAS scoresEffectiveness rate; BMD of lumbar spine—3315Zhong et al. [50], 2018——45/45Calcichew D3 tablets ± alendronate sodium tabletsAcupoint catgut embedding ± calcichew D3 tablets ± alendronate sodium tabletsVAS scoresEffectiveness rate; BMD of lumbar spine—3—16Zou et al. [53], 201866.73 ± 3.7166.27 ± 3.1860/60Caltrate D tablets ± alendronate sodium tablets ± calcitriol soft capsulesAcupoint injection ± caltrate D tablets ± alendronate sodium tablets ± calcitriol soft capsules—Effectiveness rate; BMD of femoral neck and lumbar spine; adverse effects0/06—17Ma and Fan [45], 201868.43 ± 3.6868.56 ± 3.7942/42Calcium carbonate ± vitamin D tabletsBushenzhuanggutang ± acupuncture and moxibustion ± calcium carbonate ± vitamin D tablets—Effectiveness rate—31218Lin [51], 2006 (1)——24/22Osteoform capsulesAcupoint catgut embedding ± osteoform capsules—BMD of femoral neck—6—19Lin [52], 2006 (2)——20/18Osteoform capsulesAcupoint catgut embedding ± osteoform capsules—BMD of femoral neck—6—20Qi [27], 201675.42 ± 6.8376.5 ± 7.28100/100Caltrate DBushenqianggufang ± caltrate D—Effectiveness rate; BMD of femoral neck and lumbar spine—3321Li et al. [28], 201775.4 ± 4.972.6 ± 5.530/30Calcitriol soft capsules ± caltrate D600Bushenjianpitang ± calcitriol soft capsules ± caltrate D600—Effectiveness rate—3—22Hu and Li [29], 2012——155/145Caltrate D ± miacalcicShangkeyishenjianguwan ± caltrate D ± miacalcic—BMD of lumbar spine—3623Liu and Gong [30], 201859.88 ± 7.4660.49 ± 7.2538/38Calcitriol soft capsules ± calcium carbonate D3 ± alendronate sodium tabletsBushenjianpihuoxuefang ± calcitriol soft capsules ± calcium carbonate D3 ± alendronate sodium tablets—Effectiveness rate; BMD of femoral neck and lumbar spine; adverse effects6/46—24Chen et al. [31], 201766.22 ± 11.365.12 ± 12.4132/28Salmon calcitoninBushenjiangufang ± salmon calcitoninVAS scoresEffectiveness rate—6—25Zou [32], 2016——31/31Alendronate sodium tablets ± calcichew D3 tabletsBushenjiangutang ± alendronate sodium tablets ± calcichew D3 tablets—BMD of femoral neck and lumbar spine—6—26Han [33], 201355.32 ± 1.5354.08 ± 3.2628/28Alfacalcidol soft capsules ± caltrateBushenzhuanggutang ± alfacalcidol soft capsules ± caltrate—Effectiveness rate; adverse effects0/02—27Huang et al. [34], 2018——88/88Alendronate sodium tabletsBushentang ± alendronate sodium tabletsVAS scoresEffectiveness rate; BMD of femoral neck and lumbar spine; adverse effects0/06—28Huang et al. [35], 2017/——46/46Salmon calcitoninBushenhuoxuefang ± salmon calcitonin—BMD of femoral neck and lumbar spine—6—29Song et al. [36], 201576.1 ± 3.7876.4 ± 3.5690/90Salmon calcitoninBushenhuoxuefang ± salmon calcitonin—Effectiveness rate; adverse effects0/012—30Pan and Ding [37], 201457. 2 ± 11. 256. 9 ± 11. 043/43Oyster shell calcium capsulesBushenhuoxuefang ± oyster shell calcium capsules—Effectiveness rate; BMD of femoral neck and lumbar spine; adverse effects0/43—31Wang [38], 201862.25 ± 5.0162.18 ± 4.58100/100Calcium carbonate and vitamin D3 tabletsBushenhuoxuetang ± calcium carbonate and vitamin D3 tablets—Effectiveness rate; BMD of lumbar spine—3—32Gui et al. [39], 201766.28 ± 8.1766.19 ± 8.3430/30Alendronate sodium tablets ± caltrate DBushenyiqihuayutang ± alendronate sodium tablets ± caltrate D—Effectiveness rate; BMD of total hip and lumbar spine; adverse effects4 Feb6—33Liu et al. [40], 2011 (2)59.8 ± 8.6Liu 2011 (2)∗: 62.5 ± 9.7; Liu 2011 (2): 60.3 ± 10.2A: 45/45 B: 45Calcichew D3 tablesLiu 2011 (2)∗: acupoint catgut embedding ± calcichew D3 tables; Liu 2011 (2): Xian Ling Gu Bao capsules ± calcichew D3 tablesTCM symptom integral; VAS scoresEffectiveness rate; BMD of lumbar spine—6—34Ouyang et al. [46], 201165.6 ± 6.664.4 ± 5.325/30AlendronateAcupuncture and moxibustion ± alendronateTCM symptom integralBMD of lumbar spine and proximal femur—6—35Zhou et al. [54], 201655 ± 456 ± 430/30Salmon calcitoninAcupoint injectionTCM symptom integralBMD of lumbar spine—2—36Xie et al. [41], 201861.00 ± 3.1259.40 ± 4.1230/31Vitamin D chewable tablets ± calcitriol soft capsulesGushenfang ± vitamin D chewable tablets ± calcitriol soft capsules—Effectiveness rate; adverse effects0/03—Notes: the experimental group of Liu 2011 (1) was divided into 2 groups, respectively: Liu 2011 (1) and Liu 2011 (1)∗; the experimental group of Liu 2011 (2) was divided into 2 groups, respectively: Liu 2011 (2) and Liu 2011 (2)∗; the experimental group of Liu 2011 (3) was divided into 2 groups, respectively: Liu 2011 (3) and Liu 2011 (3)∗. A: experimental group; B: control group.


### 3.2. Risk of Bias Assessment

We used the Cochrane Collaboration’s risk of bias assessment tool to assess the quality of the included studies. Firstly, all studies reported the method of randomization, and 30 studies described the method of generating a randomization number table [19–30, 32, 34, 35, 37–42, 44, 46, 48–54]. The remaining methods to achieve the sequence generation process include the following: drawing opaque envelope randomly [43], using Doll’s clinical case random table [47], drawing of lots, [36, 45], and tossing coins [31, 33]. Secondly, there were only 3 studies which achieved allocation concealment [19, 20, 43]. Thirdly, 3 studies were assessed as appropriate double-blinding of participants and provided detailed information for double-blinding during treatment as well as an outcome assessment [19, 20, 43]. None of the studies reported any incomplete outcome data (Table 3 and Figure 2).Table 3
Brief table of risk assessment.
Risk of bias assessment (yes/no/unclear)No.Included studies (first author, year)Random sequence generationAllocation concealmentBlinding of participants, personnel, and outcome assessorsIncomplete outcome dataSelective outcome reportingOther sources of bias1Zheng et al. [19], 2019Randomization number tableYesYesYesNoNo2Liu and Wang [42], 2016Randomization number tableUnclearUnclearYesNoNo3Xu et al. [43], 2018Draw opaque envelope randomlyYesYesYesNoNo4Zhu et al. [20], 2012Using a computer random number generatorYesYesYesNoNo5Zhao et al. [21], 2018Randomization number tableUnclearUnclearYesNoNo6Yuan et al. [22], 2014Randomization number tableUnclearUnclearYesNoNo7Huang [23], 2015Randomization number tableUnclearUnclearYesNoNo8Wu et al. [24], 2005Randomization number tableUnclearUnclearYesNoNo9Liu et al. [25], 2011 (3)Randomization number tableUnclearUnclearYesNoNo10Lu [47], 2014Doll’s clinical case random tableUnclearUnclearYesNoNo11Han et al. [44], 2011Randomization number tableUnclearUnclearYesNoNo12Liu et al. [26], 2011 (1)Randomization number tableUnclearUnclearYesNoNo13Peng et al. [48], 2017Randomization number tableUnclearUnclearYesNoNo14Peng et al. [49], 2018Randomization number tableUnclearUnclearYesNoNo15Zhong et al. [50], 2018Randomization number tableUnclearUnclearYesNoNo16Zou et al. [53], 2018Randomization number tableUnclearUnclearYesNoNo17Ma et al. [45], 2018Drawing of lotsUnclearUnclearYesNoNo18Lin [51], 2006 (1)Randomization number tableUnclearUnclearYesNoNo19Lin [52], 2006 (2)Randomization number tableUnclearUnclearYesNoNo20Qi [27], 2016Randomization number tableUnclearUnclearYesNoNo21Li et al. [28], 2017Randomization number tableUnclearUnclearYesNoNo22Hu and Li [29], 2012Randomization number tableUnclearUnclearYesNoNo23Liu and Gong [30], 2018Randomization number tableUnclearUnclearYesNoNo24Chen et al. [31], 2017Coin tossingUnclearUnclearYesNoNo25Zou [32], 2016Randomization number tableUnclearUnclearYesNoNo26Han [33], 2013Coin tossingUnclearUnclearYesNoNo27Huang et al. [34], 2018Randomization number tableUnclearUnclearYesNoNo28Huang et al. [35], 2017Randomization number tableUnclearUnclearYesNoNo29Song et al. [36], 2015Draw lots randomlyUnclearUnclearYesNoNo30Pan and Ding [37], 2014Randomization number tableUnclearUnclearYesNoNo31Wang [38], 2018Randomization number tableUnclearUnclearYesNoNo32Gui et al. [39], 2017Randomization number tableUnclearUnclearYesNoNo33Liu et al. [40], 2011 (2)Randomization number tableUnclearUnclearYesNoNo34Ouyang et al. [46], 2011Randomization number tableUnclearUnclearYesNoNo35Zhou et al. [54], 2016Randomization number tableUnclearUnclearYesNoNo36Xie et al. [41], 2018Randomization number tableUnclearUnclearYesNoNoFigure 2
Risk of bias assessment. Notes: the experimental group of Liu 2011 (1) was divided into 2 groups, respectively: Liu 2011 (1) and Liu 2011 (1)∗; the experimental group of Liu 2011 (2) was divided into 2 groups, respectively: Liu 2011 (2) and Liu 2011 (2)∗; the experimental group of Liu 2011 (3) was divided into 2 groups, respectively: Liu 2011 (3) and Liu 2011 (3)∗.
(a)(b)


### 3.3. Meta-Analysis

#### 3.3.1. Effectiveness Rates of Different Treatment Methods Included in TS (TK) Principle

Twenty-five RCTs reported effectiveness rates of different treatment methods included in the TS (TK) principle [21–23, 25, 27, 28, 30, 31, 33, 34, 36–42, 44–50, 53]. Sixteen RCTs reported effectiveness rates of TCM herbal medicine [21–23, 25, 27, 28, 30, 31, 33, 34, 36–41], and there was low statistical heterogeneity among studies (chi2 = 19.09, P=0.21; I2 = 21%). Therefore, the fixed-effect model was applied to calculate the combined RR and 95% CI as 1.24 (1.19, 1.30), P<0.00001, indicating a statistically significant difference between TCM herbal medicine combined with CWM and CWM alone. This result suggests that TCM herbal medicine combined with CWM in the treatment of POP can significantly improve clinical efficacy when compared with using CWM alone. Three studies reported effectiveness rates of acupuncture and moxibustion combined with TCM herbal medicine [42, 44, 45]. The result showed that there was no statistical heterogeneity among studies (chi2 = 3.94, P=0.14; I2 = 49%), so we adopted a fixed-effect model to calculate the combined RR and 95% CI as 1.34 (1.19, 1.51), P<0.00001, indicating a statistically significant difference between the experimental group and the control group. This result suggests that, in respect of effectiveness rates, using acupuncture and moxibustion combined with TCM herbal medicine plus CWM for POP was better than using CWM alone. There are 6 studies which reported effectiveness rates of acupoint catgut embedding [25, 40, 47–50]. The heterogeneity was not detected among studies (chi2 = 4.53, P=0.48; I2 = 0%), so a fixed-effect model was used to calculate the combined RR and 95% CI as 1.42 (1.27, 1.58), P<0.00001, indicating a statistically significant difference between acupoint catgut embedding combined with the CWM group and the CWM alone group. This result shows that the effectiveness rates of catgut embedding combined with CWM for POP were better than using CWM alone. There is only 1 study which reported effectiveness rates of acupoint injection [53]. The combined RR and 95% CI was 1.25 (1.05, 1.48), P<0.00001, indicating the difference between acupoint injection combined with the CWM group and the CWM alone group. Owing to the small sample size, this result would show that the effectiveness rates of acupoint injection combined with CWM for POP were better than using CWM alone. All in all, the pooled data showed that different treatment methods included in the TS (TK) principle combined with CWM were more effective than using CWM alone in improving effectiveness rates, with significant differences (RR = 1.28; 95% CI (1.23, 1.33); P<0.00001) (Figure 3(a)).Figure 3
(a) Effectiveness rates of different treatment methods included in the TS (TK) principle. (b) Effectiveness rates of different specific therapies included in TCM herbal medicine. (c) Effectiveness rates of different treatment periods. (d) BMD (lumbar spine) of different treatment periods. (e) BMD (proximal femur (femoral neck or total hip)) of different treatment periods. (f) Adverse effects. (g) TCM symptom integral. (h) VAS scores. Notes: the experimental group of Liu 2011 (2) was divided into 2 groups, respectively: Liu 2011 (2) and Liu 2011 (2)∗; the experimental group of Liu 2011 (3) was divided into 2 groups, respectively: Liu 2011 (3) and Liu 2011 (3)∗.
(a)(b)(c)(d)(e)(f)(g)(h)


#### 3.3.2. Effectiveness Rates of Different Specific Therapies Included in TCM Herbal Medicine

There were 16 studies which reported effectiveness rates of different specific therapies included in TCM herbal medicine [21–23, 25, 27, 28, 30, 31, 33, 34, 36–41]. Five studies reported the effectiveness rates of bushen huoxue therapy [23, 36–39], three studies reported the effectiveness rates of bushen zhuanggu therapy [27, 31, 33], three studies reported the effectiveness rates of bushen jianpi therapy [22, 28, 30], and five studies reported the effectiveness rates of buyi ganshen therapy [21, 25, 34, 40, 41]. The heterogeneity among these studies was chi2 = 3.07, P=0.55; I2 = 0%, chi2 = 1.05, P=0.59; I2 = 0%, chi2 = 1.16, P=0.56; I2 = 0%, and chi2 = 3.02, P=0.55; I2 = 0%, respectively. Therefore, the fixed-effect model was applied to calculate the combined RR and 95% CI. After calculating, the combined RR and 95% CI was 1.18 (1.11, 1.24); P<0.00001, 1.36 (1.21, 1.53); P<0.00001, 1.34 (1.15, 1.57); P=0.0002, and 1.21 (1.11, 1.32); P<0.00001, respectively, indicating a statistically significant difference between the experimental group and the control group. This result suggests that bushen huoxue, bushen zhuanggu, bushen jianpi, and buyi ganshen TCM herbal medicine combined with CWM in the treatment of POP can significantly improve clinical efficacy when compared with using CWM alone. The combined data showed that different specific therapies included in TCM herbal medicine combined with CWM were more effective than using CWM alone in improving effectiveness rates, with significant differences (RR = 1.23; 95% CI (1.18, 1.29); P<0.00001) (Figure 3(b)).


#### 3.3.3. Effectiveness Rates of Different Treatment Periods

Twenty-three literature studies reported effectiveness rates of different treatment periods [21–23, 26–28, 30, 31, 33, 34, 37–42, 44, 45, 47–50, 53]. Eleven literature studies reported treatment periods of less than 3 months [23, 27, 28, 37, 38, 41, 44, 45, 48–50]. However, there was high statistical heterogeneity among studies (chi2 = 22.88, P=0.01; I2 = 56%). A sensitivity analysis was performed to identify the source of heterogeneity. By removing one trial [38], no heterogeneity was detected (chi2 = 4.88, P=0.84; I2 = 0%). We confirmed the accuracy of the data without publication bias after contacting the author. So, we adopted a random-effect model to calculate the combined RR and 95% CI as 1.35 (1.27, 1.43), P<0.00001, indicating a statistically significant difference between the TS (TK) principle combined with the CWM group and the CWM alone group. It is suggested that using the TS (TK) principle combined with CWM for POP was better than using CWM alone in improving effectiveness rates when the treatment periods were less than 3 months. Twelve literature studies reported treatment periods of three to six months [21, 22, 25, 30, 31, 34, 39, 40, 42, 44, 47, 53]. There was no statistical heterogeneity among studies (chi2 = 7.92, P=0.85; I2 = 0%). Therefore, the fixed-effect model was applied to calculate the combined RR and 95% CI as 1.25 (1.18, 1.32), P<0.00001, indicating a statistically significant difference between the TS (TK) principle combined with the CWM group and the CWM alone group. It is suggested that using the TS (TK) principle combined with CWM for POP was better than using CWM alone in improving effectiveness rates when the treatment periods were three to six months. The pooled data showed that different treatment periods combined with CWM were more effective than using CWM alone in improving effectiveness rates, with significant differences (RR = 1.29; 95% CI (1.24, 1.35); P<0.00001) (Figure 3(c)).


#### 3.3.4. BMD (Lumbar Spine) of Different Treatment Periods

Twenty-one studies reported BMD (lumbar spine) of different treatment periods [20, 21, 24, 25, 27, 29, 30, 32, 34, 35, 37–40, 42, 46, 48–50, 53, 54]. There were 8 studies which reported BMD (lumbar spine) of less than 3 months [27, 29, 37, 38, 48–50, 54], and 11 studies reported BMD (lumbar spine) of three to six months [21, 25, 30, 32, 34, 35, 39, 40, 42, 46, 53]. However, we detected high statistical heterogeneity among studies, chi2 = 40.14, P<0.00001; I2 = 83% and chi2 = 69.18, P<0.00001; I2 = 83%. The source of heterogeneity may be related to different treatment methods. Therefore, we adopted the random-effect model, and meta-analysis showed that there was a significant difference between the experimental and control groups (SMD = 0.83; 95% CI (0.52, 1.15); P<0.00001 and SMD = 0.56; 95% CI (0.27, 0.85); P<0.00001). It is suggested that using the TS (TK) principle combined with CWM less than three months or three to six months can both improve the BMD of the lumbar spine and is better than using CWM alone. Two studies reported BMD (lumbar spine) of more than six months [20, 24], and there was high statistical heterogeneity among studies (chi2 = 49.53, P<0.00001; I2 = 98%). We adopted the random-effect model, and meta-analysis showed that there was no significant difference between the experimental and control groups (SMD = 1.36; 95% CI (−1.33, 4.0); P=0.32). In general, the meta-analysis showed that different treatment periods combined with CWM were more effective than using CWM alone in improving the BMD of the lumbar spine, with significant differences (SMD = 0.71; 95% CI (0.47, 0.95); P<0.00001) (Figure 3(d)).


#### 3.3.5. BMD (Proximal Femur (Femoral Neck or Total Hip)) of Different Treatment Periods

There were 15 studies which reported BMD (proximal femur (femoral neck or total hip)) of different treatment periods [19, 20, 24, 27, 30, 32, 34, 35, 37, 39, 42, 46, 51–53]. Two studies reported BMD (proximal femur (femoral neck or total hip)) of less than 3 months [27, 37]. High statistical heterogeneity among studies was detected (chi2 = 10.41, P=0.001; I2 = 90%); therefore, we adopted the random-effect model, and meta-analysis showed that there was no significant difference between the experimental and control groups (SMD = 0.53; 95% CI (−0.30, 1.36); P=0.21). Ten studies reported BMD (proximal femur (femoral neck or total hip)) of three to six months [30, 32, 34, 35, 39, 42, 46, 51–53]. There was high statistical heterogeneity among studies (chi2 = 52.61, P<0.00001; I2 = 83%). We performed sensitivity analysis by removing one trial [35], and low heterogeneity was detected (chi2 = 11.68, P=0.17; I2 = 32%). The source of heterogeneity may be related to different treatment methods. So, a random-effect model was adopted. The results showed that using the TS (TK) principle combined with CWM three to six months can improve the BMD of the proximal femur (femoral neck or total hip) and was better than using CWM alone (SMD = 0.69; 95% CI (0.34, 1.04); P<0.00001). Three studies reported BMD of more than six months, and these showed that there was high heterogeneity (chi2 = 135.92, P<0.00001; I2 = 99%) [19, 20, 24]. By removing one study [20], no heterogeneity was detected. The high heterogeneity may result from different treatment methods adopted by these studies. Thus, a random-effect model was adopted, and the results showed that there was no significant difference between the experimental and control groups (SMD = 2.06; 95% CI (0.36, 4.49); P=0.10). The combined data showed that different treatment periods combined with CWM were more effective than using CWM alone in improving the BMD of the proximal femur (femoral neck or total hip), with significant differences (SMD = 0.94; 95% CI (0.49, 1.38); P<0.00001) (Figure 3(e)).


#### 3.3.6. Adverse Effects

Eleven studies reported adverse effects [19–21, 30, 33, 34, 36, 37, 39, 41, 53], and there was no statistical heterogeneity among studies (chi2 = 4.07, P=0.54; I2 = 0%). Hence, the fixed-effect model was applied to calculate the combined RR and 95% CI as 0.99 (0.65, 1.51), P=0.97, indicating no statistically significant difference between the experimental group and the control group. This result suggests that the TS (TK) principle combined with CWM or using CWM alone in the treatment of POP are both safe. Besides, the common adverse effects in the experimental group were gastrointestinal complaints, liver enzyme abnormal, hypertension, joint pain, stomach discomfort, nausea, vomiting, headache, musculoskeletal pain, etc. The adverse effects in the control group included gastrointestinal complaints, liver enzyme abnormal, hypertension, nausea, and vomiting (Figure 3(f)).


#### 3.3.7. TCM Symptom Integral

The TCM symptom integral was established according to theClinical Research Guidance of New Chinese Herbal Medicine [55]. Four studies reported TCM symptom integral [26, 40, 46, 54], and there was low statistical heterogeneity among studies (chi2 = 7.49, P=0.19; I2 = 33%). Therefore, the fixed-effect model was applied. The meta-analysis showed that there was a statistically significant difference between the experimental group and the control group (SMD = −1.23; 95% CI (−1.43, −1.02); P<0.00001). This result suggests that the TS (TK) principle combined with CWM in the treatment of POP can significantly improve TCM symptom integral when compared with using CWM alone (Figure 3(g)).


#### 3.3.8. VAS Scores

There were 10 studies which reported VAS scores [21, 23, 25, 31, 34, 40, 43, 48–50]. The result showed that there was high statistical heterogeneity among studies (chi2 = 733.80, P<0.00001; I2 = 99%), so we adopted a random-effect model. The combined data showed that there was a statistically significant difference between the experimental group and the control group (SMD = −3.88; 95% CI (−5.29, −2.46); P<0.00001). This result suggests that the TS (TK) principle combined with CWM in the treatment of POP was more effective than using CWM alone in improving VAS scores (Figure 3(h)).


#### 3.3.9. Publication Bias

The funnel plots were generated for studies with data on the effectiveness rates of different treatment methods included in the TS (TK) principle. The results showed that most of the points in the funnel plots were symmetrical. However, two points were outside the 95% CIs, which indicates that there may have been publication bias in our studies and that might influence the results of our analysis, as can be seen in Figure4.Figure 4
Funnel plot of effectiveness rates of different treatment methods included in the TS (TK) principle.


#### 3.3.10. Quality of Evidence

There were 8 results for levels of evidence in our study. The detailed GRADE evidence profile of results is shown in Figure5.Figure 5
GRADE evidence profile.


## 3.1. Study Description and Participants

We obtained 390 relevant studies through preliminary searches. After multiple filtering steps, 36 RCTs with a total of 3617 participants were ultimately included in this systematic review. The flowchart of all study selection procedures is shown in Figure1.Figure 1
The flowchart of the selection procedure.The 36 included studies involved 3617 participants. Among these studies, apart from combined with CWM, 23 studies reported using TCM herbal medicine [19–41], 5 studies reported using acupuncture and moxibustion combined with traditional Chinese herbal medicine [42–46], 9 studies reported using acupoint catgut embedding [25, 26, 40, 47–52], and 2 studies reported using acupoint injection [53, 54]. Besides, 3 studies divided their experimental group into two groups, respectively (acupoint catgut embedding group and TCM herbal medicine group) [25, 26, 40]. The detailed characteristics of the included studies are shown in Table 2.Table 2
Characteristics of the included studies.
No.Included studies (author, year)Age (years)Participants (experimental group/control group)InterventionOutcomesAdverse effects (experimental group/control)Treatment periods (months)Follow-up (months)Control groupExperimental groupControl groupExperimental groupSecondary outcomesPrimary outcomes1Zheng et al. [19], 201963.9 ± 2.8163.91 ± 2.8670/70Placebo capsules ± calcium carbonateBushen Yijing Fang ± calcium carbonate—BMD of femoral neck; adverse effects9/8361202Liu and Wang [42], 201656.15 ± 6.7755.86 ± 6.9262/62Alendronate sodium tablets ± calcium carbonate D3 tabletsErxian Bushen decoction ± acupuncture and moxibustion ± alendronate sodium tablets ± calcium carbonate D3 tablets—Effectiveness rate; BMD of femoral neck and lumbar spine—6—3Xu et al. [43], 201863.90 ± 7.5965.16 ± 6.8232/31Calcium carbonate D3Thunder-fire moxibustion ± calcium carbonate D3VAS scores——114Zhu et al. [20], 201264.9 ± 6.065.4 ± 6.361/61Calcium carbonate ± vitamin DXian Ling Gu Bao capsules ± calcium carbonate ± vitamin D—BMD of femoral neck and lumbar spine; adverse effects11/1112125Zhao and Yan [21], 201861.3 ± 4.162.1 ± 4.150/50Caltrate ± alpha D3 calciferolTraditional Chinese medicine prescription ± caltrate ± alpha D3 calciferolVAS scoresEffectiveness rate; BMD of lumbar spine (L2–4); adverse effects9/6666Yuan et al. [22], 2014——40/40Alendronate ± calcium carbonate D3Chinese herbal medicine ± alendronate ± calcium carbonate D3—Effectiveness rate—6—7Huang [23], 201565.5 ± 1.665.7 ± 1.570/70Calcium carbonate D3 ± alfacalcidol soft capsulesBushenhuoxuetang ± calcium carbonate D3 ± alfacalcidol soft capsulesVAS scoresEffectiveness rate—2—8Wu et al. [24], 200556.4 ± 4.655.6 ± 4.334/34Caltrate D600Xian Ling Gu Bao capsules ± caltrate D600—BMD of femoral neck and lumbar spine—12—9Liu et al. [25], 2011 (3)62.8 ± 5.9Liu 2011 (3)∗: 63.7 ± 3.8; Liu 2011 (3): 61.8 ± 8.3A: 35/35; B: 35Calcichew D3 tabletsLiu 2011 (3)∗: acupoint catgut embedding ± calcichew D3 tablets; Liu 2011 (3): Xianling Gubao capsules ± calcichew D3 tabletsVAS scoresEffectiveness rate; BMD of lumbar spine—6—10Lu [47], 201462.14 ± 6.3460.84 ± 6.9525/22Calcium carbonate D3Acupoint catgut embedding ± calcium carbonate D3—Effectiveness rate—6—11Han et al. [44], 201167.39 ± 4. 0567.42 ± 3. 8930/30CaltrateShuganwenshentanyushuangjietang ± acupuncture and moxibustion ± caltrate—Effectiveness rate—6—12Liu et al. [26], 2011 (1)62.8 ± 5.9Liu 2011 (1)∗: 63.7 ± 3.8; Liu 2011 (1): 61.8 ± 8.3A: 35/35 B: 35Calcichew D3 tabletsLiu 2011 (1)∗: acupoint catgut embedding ± calcichew D3 tablets; Liu 2011 (1): Xian Ling Gu Bao capsules ± calcichew D3 tabletsTCM symptom integral—0/0/46—13Peng et al. [48], 2017——35/35Calcichew D3 tablets ± alendronate sodium tabletsAcupoint catgut embedding ± calcichew D3 tablets ± alendronate sodium tabletsVAS scoresEffectiveness rate; BMD of lumbar spine—3—14Peng et al. [49], 2018——45/45Calcichew D3 tablets ± alendronate sodium tabletsAcupoint catgut embedding ± calcichew D3 tablets ± alendronate sodium tabletsVAS scoresEffectiveness rate; BMD of lumbar spine—3315Zhong et al. [50], 2018——45/45Calcichew D3 tablets ± alendronate sodium tabletsAcupoint catgut embedding ± calcichew D3 tablets ± alendronate sodium tabletsVAS scoresEffectiveness rate; BMD of lumbar spine—3—16Zou et al. [53], 201866.73 ± 3.7166.27 ± 3.1860/60Caltrate D tablets ± alendronate sodium tablets ± calcitriol soft capsulesAcupoint injection ± caltrate D tablets ± alendronate sodium tablets ± calcitriol soft capsules—Effectiveness rate; BMD of femoral neck and lumbar spine; adverse effects0/06—17Ma and Fan [45], 201868.43 ± 3.6868.56 ± 3.7942/42Calcium carbonate ± vitamin D tabletsBushenzhuanggutang ± acupuncture and moxibustion ± calcium carbonate ± vitamin D tablets—Effectiveness rate—31218Lin [51], 2006 (1)——24/22Osteoform capsulesAcupoint catgut embedding ± osteoform capsules—BMD of femoral neck—6—19Lin [52], 2006 (2)——20/18Osteoform capsulesAcupoint catgut embedding ± osteoform capsules—BMD of femoral neck—6—20Qi [27], 201675.42 ± 6.8376.5 ± 7.28100/100Caltrate DBushenqianggufang ± caltrate D—Effectiveness rate; BMD of femoral neck and lumbar spine—3321Li et al. [28], 201775.4 ± 4.972.6 ± 5.530/30Calcitriol soft capsules ± caltrate D600Bushenjianpitang ± calcitriol soft capsules ± caltrate D600—Effectiveness rate—3—22Hu and Li [29], 2012——155/145Caltrate D ± miacalcicShangkeyishenjianguwan ± caltrate D ± miacalcic—BMD of lumbar spine—3623Liu and Gong [30], 201859.88 ± 7.4660.49 ± 7.2538/38Calcitriol soft capsules ± calcium carbonate D3 ± alendronate sodium tabletsBushenjianpihuoxuefang ± calcitriol soft capsules ± calcium carbonate D3 ± alendronate sodium tablets—Effectiveness rate; BMD of femoral neck and lumbar spine; adverse effects6/46—24Chen et al. [31], 201766.22 ± 11.365.12 ± 12.4132/28Salmon calcitoninBushenjiangufang ± salmon calcitoninVAS scoresEffectiveness rate—6—25Zou [32], 2016——31/31Alendronate sodium tablets ± calcichew D3 tabletsBushenjiangutang ± alendronate sodium tablets ± calcichew D3 tablets—BMD of femoral neck and lumbar spine—6—26Han [33], 201355.32 ± 1.5354.08 ± 3.2628/28Alfacalcidol soft capsules ± caltrateBushenzhuanggutang ± alfacalcidol soft capsules ± caltrate—Effectiveness rate; adverse effects0/02—27Huang et al. [34], 2018——88/88Alendronate sodium tabletsBushentang ± alendronate sodium tabletsVAS scoresEffectiveness rate; BMD of femoral neck and lumbar spine; adverse effects0/06—28Huang et al. [35], 2017/——46/46Salmon calcitoninBushenhuoxuefang ± salmon calcitonin—BMD of femoral neck and lumbar spine—6—29Song et al. [36], 201576.1 ± 3.7876.4 ± 3.5690/90Salmon calcitoninBushenhuoxuefang ± salmon calcitonin—Effectiveness rate; adverse effects0/012—30Pan and Ding [37], 201457. 2 ± 11. 256. 9 ± 11. 043/43Oyster shell calcium capsulesBushenhuoxuefang ± oyster shell calcium capsules—Effectiveness rate; BMD of femoral neck and lumbar spine; adverse effects0/43—31Wang [38], 201862.25 ± 5.0162.18 ± 4.58100/100Calcium carbonate and vitamin D3 tabletsBushenhuoxuetang ± calcium carbonate and vitamin D3 tablets—Effectiveness rate; BMD of lumbar spine—3—32Gui et al. [39], 201766.28 ± 8.1766.19 ± 8.3430/30Alendronate sodium tablets ± caltrate DBushenyiqihuayutang ± alendronate sodium tablets ± caltrate D—Effectiveness rate; BMD of total hip and lumbar spine; adverse effects4 Feb6—33Liu et al. [40], 2011 (2)59.8 ± 8.6Liu 2011 (2)∗: 62.5 ± 9.7; Liu 2011 (2): 60.3 ± 10.2A: 45/45 B: 45Calcichew D3 tablesLiu 2011 (2)∗: acupoint catgut embedding ± calcichew D3 tables; Liu 2011 (2): Xian Ling Gu Bao capsules ± calcichew D3 tablesTCM symptom integral; VAS scoresEffectiveness rate; BMD of lumbar spine—6—34Ouyang et al. [46], 201165.6 ± 6.664.4 ± 5.325/30AlendronateAcupuncture and moxibustion ± alendronateTCM symptom integralBMD of lumbar spine and proximal femur—6—35Zhou et al. [54], 201655 ± 456 ± 430/30Salmon calcitoninAcupoint injectionTCM symptom integralBMD of lumbar spine—2—36Xie et al. [41], 201861.00 ± 3.1259.40 ± 4.1230/31Vitamin D chewable tablets ± calcitriol soft capsulesGushenfang ± vitamin D chewable tablets ± calcitriol soft capsules—Effectiveness rate; adverse effects0/03—Notes: the experimental group of Liu 2011 (1) was divided into 2 groups, respectively: Liu 2011 (1) and Liu 2011 (1)∗; the experimental group of Liu 2011 (2) was divided into 2 groups, respectively: Liu 2011 (2) and Liu 2011 (2)∗; the experimental group of Liu 2011 (3) was divided into 2 groups, respectively: Liu 2011 (3) and Liu 2011 (3)∗. A: experimental group; B: control group.


## 3.2. Risk of Bias Assessment

We used the Cochrane Collaboration’s risk of bias assessment tool to assess the quality of the included studies. Firstly, all studies reported the method of randomization, and 30 studies described the method of generating a randomization number table [19–30, 32, 34, 35, 37–42, 44, 46, 48–54]. The remaining methods to achieve the sequence generation process include the following: drawing opaque envelope randomly [43], using Doll’s clinical case random table [47], drawing of lots, [36, 45], and tossing coins [31, 33]. Secondly, there were only 3 studies which achieved allocation concealment [19, 20, 43]. Thirdly, 3 studies were assessed as appropriate double-blinding of participants and provided detailed information for double-blinding during treatment as well as an outcome assessment [19, 20, 43]. None of the studies reported any incomplete outcome data (Table 3 and Figure 2).Table 3
Brief table of risk assessment.
Risk of bias assessment (yes/no/unclear)No.Included studies (first author, year)Random sequence generationAllocation concealmentBlinding of participants, personnel, and outcome assessorsIncomplete outcome dataSelective outcome reportingOther sources of bias1Zheng et al. [19], 2019Randomization number tableYesYesYesNoNo2Liu and Wang [42], 2016Randomization number tableUnclearUnclearYesNoNo3Xu et al. [43], 2018Draw opaque envelope randomlyYesYesYesNoNo4Zhu et al. [20], 2012Using a computer random number generatorYesYesYesNoNo5Zhao et al. [21], 2018Randomization number tableUnclearUnclearYesNoNo6Yuan et al. [22], 2014Randomization number tableUnclearUnclearYesNoNo7Huang [23], 2015Randomization number tableUnclearUnclearYesNoNo8Wu et al. [24], 2005Randomization number tableUnclearUnclearYesNoNo9Liu et al. [25], 2011 (3)Randomization number tableUnclearUnclearYesNoNo10Lu [47], 2014Doll’s clinical case random tableUnclearUnclearYesNoNo11Han et al. [44], 2011Randomization number tableUnclearUnclearYesNoNo12Liu et al. [26], 2011 (1)Randomization number tableUnclearUnclearYesNoNo13Peng et al. [48], 2017Randomization number tableUnclearUnclearYesNoNo14Peng et al. [49], 2018Randomization number tableUnclearUnclearYesNoNo15Zhong et al. [50], 2018Randomization number tableUnclearUnclearYesNoNo16Zou et al. [53], 2018Randomization number tableUnclearUnclearYesNoNo17Ma et al. [45], 2018Drawing of lotsUnclearUnclearYesNoNo18Lin [51], 2006 (1)Randomization number tableUnclearUnclearYesNoNo19Lin [52], 2006 (2)Randomization number tableUnclearUnclearYesNoNo20Qi [27], 2016Randomization number tableUnclearUnclearYesNoNo21Li et al. [28], 2017Randomization number tableUnclearUnclearYesNoNo22Hu and Li [29], 2012Randomization number tableUnclearUnclearYesNoNo23Liu and Gong [30], 2018Randomization number tableUnclearUnclearYesNoNo24Chen et al. [31], 2017Coin tossingUnclearUnclearYesNoNo25Zou [32], 2016Randomization number tableUnclearUnclearYesNoNo26Han [33], 2013Coin tossingUnclearUnclearYesNoNo27Huang et al. [34], 2018Randomization number tableUnclearUnclearYesNoNo28Huang et al. [35], 2017Randomization number tableUnclearUnclearYesNoNo29Song et al. [36], 2015Draw lots randomlyUnclearUnclearYesNoNo30Pan and Ding [37], 2014Randomization number tableUnclearUnclearYesNoNo31Wang [38], 2018Randomization number tableUnclearUnclearYesNoNo32Gui et al. [39], 2017Randomization number tableUnclearUnclearYesNoNo33Liu et al. [40], 2011 (2)Randomization number tableUnclearUnclearYesNoNo34Ouyang et al. [46], 2011Randomization number tableUnclearUnclearYesNoNo35Zhou et al. [54], 2016Randomization number tableUnclearUnclearYesNoNo36Xie et al. [41], 2018Randomization number tableUnclearUnclearYesNoNoFigure 2
Risk of bias assessment. Notes: the experimental group of Liu 2011 (1) was divided into 2 groups, respectively: Liu 2011 (1) and Liu 2011 (1)∗; the experimental group of Liu 2011 (2) was divided into 2 groups, respectively: Liu 2011 (2) and Liu 2011 (2)∗; the experimental group of Liu 2011 (3) was divided into 2 groups, respectively: Liu 2011 (3) and Liu 2011 (3)∗.
(a)(b)


## 3.3. Meta-Analysis

### 3.3.1. Effectiveness Rates of Different Treatment Methods Included in TS (TK) Principle

Twenty-five RCTs reported effectiveness rates of different treatment methods included in the TS (TK) principle [21–23, 25, 27, 28, 30, 31, 33, 34, 36–42, 44–50, 53]. Sixteen RCTs reported effectiveness rates of TCM herbal medicine [21–23, 25, 27, 28, 30, 31, 33, 34, 36–41], and there was low statistical heterogeneity among studies (chi2 = 19.09, P=0.21; I2 = 21%). Therefore, the fixed-effect model was applied to calculate the combined RR and 95% CI as 1.24 (1.19, 1.30), P<0.00001, indicating a statistically significant difference between TCM herbal medicine combined with CWM and CWM alone. This result suggests that TCM herbal medicine combined with CWM in the treatment of POP can significantly improve clinical efficacy when compared with using CWM alone. Three studies reported effectiveness rates of acupuncture and moxibustion combined with TCM herbal medicine [42, 44, 45]. The result showed that there was no statistical heterogeneity among studies (chi2 = 3.94, P=0.14; I2 = 49%), so we adopted a fixed-effect model to calculate the combined RR and 95% CI as 1.34 (1.19, 1.51), P<0.00001, indicating a statistically significant difference between the experimental group and the control group. This result suggests that, in respect of effectiveness rates, using acupuncture and moxibustion combined with TCM herbal medicine plus CWM for POP was better than using CWM alone. There are 6 studies which reported effectiveness rates of acupoint catgut embedding [25, 40, 47–50]. The heterogeneity was not detected among studies (chi2 = 4.53, P=0.48; I2 = 0%), so a fixed-effect model was used to calculate the combined RR and 95% CI as 1.42 (1.27, 1.58), P<0.00001, indicating a statistically significant difference between acupoint catgut embedding combined with the CWM group and the CWM alone group. This result shows that the effectiveness rates of catgut embedding combined with CWM for POP were better than using CWM alone. There is only 1 study which reported effectiveness rates of acupoint injection [53]. The combined RR and 95% CI was 1.25 (1.05, 1.48), P<0.00001, indicating the difference between acupoint injection combined with the CWM group and the CWM alone group. Owing to the small sample size, this result would show that the effectiveness rates of acupoint injection combined with CWM for POP were better than using CWM alone. All in all, the pooled data showed that different treatment methods included in the TS (TK) principle combined with CWM were more effective than using CWM alone in improving effectiveness rates, with significant differences (RR = 1.28; 95% CI (1.23, 1.33); P<0.00001) (Figure 3(a)).Figure 3
(a) Effectiveness rates of different treatment methods included in the TS (TK) principle. (b) Effectiveness rates of different specific therapies included in TCM herbal medicine. (c) Effectiveness rates of different treatment periods. (d) BMD (lumbar spine) of different treatment periods. (e) BMD (proximal femur (femoral neck or total hip)) of different treatment periods. (f) Adverse effects. (g) TCM symptom integral. (h) VAS scores. Notes: the experimental group of Liu 2011 (2) was divided into 2 groups, respectively: Liu 2011 (2) and Liu 2011 (2)∗; the experimental group of Liu 2011 (3) was divided into 2 groups, respectively: Liu 2011 (3) and Liu 2011 (3)∗.
(a)(b)(c)(d)(e)(f)(g)(h)


### 3.3.2. Effectiveness Rates of Different Specific Therapies Included in TCM Herbal Medicine

There were 16 studies which reported effectiveness rates of different specific therapies included in TCM herbal medicine [21–23, 25, 27, 28, 30, 31, 33, 34, 36–41]. Five studies reported the effectiveness rates of bushen huoxue therapy [23, 36–39], three studies reported the effectiveness rates of bushen zhuanggu therapy [27, 31, 33], three studies reported the effectiveness rates of bushen jianpi therapy [22, 28, 30], and five studies reported the effectiveness rates of buyi ganshen therapy [21, 25, 34, 40, 41]. The heterogeneity among these studies was chi2 = 3.07, P=0.55; I2 = 0%, chi2 = 1.05, P=0.59; I2 = 0%, chi2 = 1.16, P=0.56; I2 = 0%, and chi2 = 3.02, P=0.55; I2 = 0%, respectively. Therefore, the fixed-effect model was applied to calculate the combined RR and 95% CI. After calculating, the combined RR and 95% CI was 1.18 (1.11, 1.24); P<0.00001, 1.36 (1.21, 1.53); P<0.00001, 1.34 (1.15, 1.57); P=0.0002, and 1.21 (1.11, 1.32); P<0.00001, respectively, indicating a statistically significant difference between the experimental group and the control group. This result suggests that bushen huoxue, bushen zhuanggu, bushen jianpi, and buyi ganshen TCM herbal medicine combined with CWM in the treatment of POP can significantly improve clinical efficacy when compared with using CWM alone. The combined data showed that different specific therapies included in TCM herbal medicine combined with CWM were more effective than using CWM alone in improving effectiveness rates, with significant differences (RR = 1.23; 95% CI (1.18, 1.29); P<0.00001) (Figure 3(b)).


### 3.3.3. Effectiveness Rates of Different Treatment Periods

Twenty-three literature studies reported effectiveness rates of different treatment periods [21–23, 26–28, 30, 31, 33, 34, 37–42, 44, 45, 47–50, 53]. Eleven literature studies reported treatment periods of less than 3 months [23, 27, 28, 37, 38, 41, 44, 45, 48–50]. However, there was high statistical heterogeneity among studies (chi2 = 22.88, P=0.01; I2 = 56%). A sensitivity analysis was performed to identify the source of heterogeneity. By removing one trial [38], no heterogeneity was detected (chi2 = 4.88, P=0.84; I2 = 0%). We confirmed the accuracy of the data without publication bias after contacting the author. So, we adopted a random-effect model to calculate the combined RR and 95% CI as 1.35 (1.27, 1.43), P<0.00001, indicating a statistically significant difference between the TS (TK) principle combined with the CWM group and the CWM alone group. It is suggested that using the TS (TK) principle combined with CWM for POP was better than using CWM alone in improving effectiveness rates when the treatment periods were less than 3 months. Twelve literature studies reported treatment periods of three to six months [21, 22, 25, 30, 31, 34, 39, 40, 42, 44, 47, 53]. There was no statistical heterogeneity among studies (chi2 = 7.92, P=0.85; I2 = 0%). Therefore, the fixed-effect model was applied to calculate the combined RR and 95% CI as 1.25 (1.18, 1.32), P<0.00001, indicating a statistically significant difference between the TS (TK) principle combined with the CWM group and the CWM alone group. It is suggested that using the TS (TK) principle combined with CWM for POP was better than using CWM alone in improving effectiveness rates when the treatment periods were three to six months. The pooled data showed that different treatment periods combined with CWM were more effective than using CWM alone in improving effectiveness rates, with significant differences (RR = 1.29; 95% CI (1.24, 1.35); P<0.00001) (Figure 3(c)).


### 3.3.4. BMD (Lumbar Spine) of Different Treatment Periods

Twenty-one studies reported BMD (lumbar spine) of different treatment periods [20, 21, 24, 25, 27, 29, 30, 32, 34, 35, 37–40, 42, 46, 48–50, 53, 54]. There were 8 studies which reported BMD (lumbar spine) of less than 3 months [27, 29, 37, 38, 48–50, 54], and 11 studies reported BMD (lumbar spine) of three to six months [21, 25, 30, 32, 34, 35, 39, 40, 42, 46, 53]. However, we detected high statistical heterogeneity among studies, chi2 = 40.14, P<0.00001; I2 = 83% and chi2 = 69.18, P<0.00001; I2 = 83%. The source of heterogeneity may be related to different treatment methods. Therefore, we adopted the random-effect model, and meta-analysis showed that there was a significant difference between the experimental and control groups (SMD = 0.83; 95% CI (0.52, 1.15); P<0.00001 and SMD = 0.56; 95% CI (0.27, 0.85); P<0.00001). It is suggested that using the TS (TK) principle combined with CWM less than three months or three to six months can both improve the BMD of the lumbar spine and is better than using CWM alone. Two studies reported BMD (lumbar spine) of more than six months [20, 24], and there was high statistical heterogeneity among studies (chi2 = 49.53, P<0.00001; I2 = 98%). We adopted the random-effect model, and meta-analysis showed that there was no significant difference between the experimental and control groups (SMD = 1.36; 95% CI (−1.33, 4.0); P=0.32). In general, the meta-analysis showed that different treatment periods combined with CWM were more effective than using CWM alone in improving the BMD of the lumbar spine, with significant differences (SMD = 0.71; 95% CI (0.47, 0.95); P<0.00001) (Figure 3(d)).


### 3.3.5. BMD (Proximal Femur (Femoral Neck or Total Hip)) of Different Treatment Periods

There were 15 studies which reported BMD (proximal femur (femoral neck or total hip)) of different treatment periods [19, 20, 24, 27, 30, 32, 34, 35, 37, 39, 42, 46, 51–53]. Two studies reported BMD (proximal femur (femoral neck or total hip)) of less than 3 months [27, 37]. High statistical heterogeneity among studies was detected (chi2 = 10.41, P=0.001; I2 = 90%); therefore, we adopted the random-effect model, and meta-analysis showed that there was no significant difference between the experimental and control groups (SMD = 0.53; 95% CI (−0.30, 1.36); P=0.21). Ten studies reported BMD (proximal femur (femoral neck or total hip)) of three to six months [30, 32, 34, 35, 39, 42, 46, 51–53]. There was high statistical heterogeneity among studies (chi2 = 52.61, P<0.00001; I2 = 83%). We performed sensitivity analysis by removing one trial [35], and low heterogeneity was detected (chi2 = 11.68, P=0.17; I2 = 32%). The source of heterogeneity may be related to different treatment methods. So, a random-effect model was adopted. The results showed that using the TS (TK) principle combined with CWM three to six months can improve the BMD of the proximal femur (femoral neck or total hip) and was better than using CWM alone (SMD = 0.69; 95% CI (0.34, 1.04); P<0.00001). Three studies reported BMD of more than six months, and these showed that there was high heterogeneity (chi2 = 135.92, P<0.00001; I2 = 99%) [19, 20, 24]. By removing one study [20], no heterogeneity was detected. The high heterogeneity may result from different treatment methods adopted by these studies. Thus, a random-effect model was adopted, and the results showed that there was no significant difference between the experimental and control groups (SMD = 2.06; 95% CI (0.36, 4.49); P=0.10). The combined data showed that different treatment periods combined with CWM were more effective than using CWM alone in improving the BMD of the proximal femur (femoral neck or total hip), with significant differences (SMD = 0.94; 95% CI (0.49, 1.38); P<0.00001) (Figure 3(e)).


### 3.3.6. Adverse Effects

Eleven studies reported adverse effects [19–21, 30, 33, 34, 36, 37, 39, 41, 53], and there was no statistical heterogeneity among studies (chi2 = 4.07, P=0.54; I2 = 0%). Hence, the fixed-effect model was applied to calculate the combined RR and 95% CI as 0.99 (0.65, 1.51), P=0.97, indicating no statistically significant difference between the experimental group and the control group. This result suggests that the TS (TK) principle combined with CWM or using CWM alone in the treatment of POP are both safe. Besides, the common adverse effects in the experimental group were gastrointestinal complaints, liver enzyme abnormal, hypertension, joint pain, stomach discomfort, nausea, vomiting, headache, musculoskeletal pain, etc. The adverse effects in the control group included gastrointestinal complaints, liver enzyme abnormal, hypertension, nausea, and vomiting (Figure 3(f)).


### 3.3.7. TCM Symptom Integral

The TCM symptom integral was established according to theClinical Research Guidance of New Chinese Herbal Medicine [55]. Four studies reported TCM symptom integral [26, 40, 46, 54], and there was low statistical heterogeneity among studies (chi2 = 7.49, P=0.19; I2 = 33%). Therefore, the fixed-effect model was applied. The meta-analysis showed that there was a statistically significant difference between the experimental group and the control group (SMD = −1.23; 95% CI (−1.43, −1.02); P<0.00001). This result suggests that the TS (TK) principle combined with CWM in the treatment of POP can significantly improve TCM symptom integral when compared with using CWM alone (Figure 3(g)).


### 3.3.8. VAS Scores

There were 10 studies which reported VAS scores [21, 23, 25, 31, 34, 40, 43, 48–50]. The result showed that there was high statistical heterogeneity among studies (chi2 = 733.80, P<0.00001; I2 = 99%), so we adopted a random-effect model. The combined data showed that there was a statistically significant difference between the experimental group and the control group (SMD = −3.88; 95% CI (−5.29, −2.46); P<0.00001). This result suggests that the TS (TK) principle combined with CWM in the treatment of POP was more effective than using CWM alone in improving VAS scores (Figure 3(h)).


### 3.3.9. Publication Bias

The funnel plots were generated for studies with data on the effectiveness rates of different treatment methods included in the TS (TK) principle. The results showed that most of the points in the funnel plots were symmetrical. However, two points were outside the 95% CIs, which indicates that there may have been publication bias in our studies and that might influence the results of our analysis, as can be seen in Figure4.Figure 4
Funnel plot of effectiveness rates of different treatment methods included in the TS (TK) principle.


### 3.3.10. Quality of Evidence

There were 8 results for levels of evidence in our study. The detailed GRADE evidence profile of results is shown in Figure5.Figure 5
GRADE evidence profile.


## 3.3.1. Effectiveness Rates of Different Treatment Methods Included in TS (TK) Principle

Twenty-five RCTs reported effectiveness rates of different treatment methods included in the TS (TK) principle [21–23, 25, 27, 28, 30, 31, 33, 34, 36–42, 44–50, 53]. Sixteen RCTs reported effectiveness rates of TCM herbal medicine [21–23, 25, 27, 28, 30, 31, 33, 34, 36–41], and there was low statistical heterogeneity among studies (chi2 = 19.09, P=0.21; I2 = 21%). Therefore, the fixed-effect model was applied to calculate the combined RR and 95% CI as 1.24 (1.19, 1.30), P<0.00001, indicating a statistically significant difference between TCM herbal medicine combined with CWM and CWM alone. This result suggests that TCM herbal medicine combined with CWM in the treatment of POP can significantly improve clinical efficacy when compared with using CWM alone. Three studies reported effectiveness rates of acupuncture and moxibustion combined with TCM herbal medicine [42, 44, 45]. The result showed that there was no statistical heterogeneity among studies (chi2 = 3.94, P=0.14; I2 = 49%), so we adopted a fixed-effect model to calculate the combined RR and 95% CI as 1.34 (1.19, 1.51), P<0.00001, indicating a statistically significant difference between the experimental group and the control group. This result suggests that, in respect of effectiveness rates, using acupuncture and moxibustion combined with TCM herbal medicine plus CWM for POP was better than using CWM alone. There are 6 studies which reported effectiveness rates of acupoint catgut embedding [25, 40, 47–50]. The heterogeneity was not detected among studies (chi2 = 4.53, P=0.48; I2 = 0%), so a fixed-effect model was used to calculate the combined RR and 95% CI as 1.42 (1.27, 1.58), P<0.00001, indicating a statistically significant difference between acupoint catgut embedding combined with the CWM group and the CWM alone group. This result shows that the effectiveness rates of catgut embedding combined with CWM for POP were better than using CWM alone. There is only 1 study which reported effectiveness rates of acupoint injection [53]. The combined RR and 95% CI was 1.25 (1.05, 1.48), P<0.00001, indicating the difference between acupoint injection combined with the CWM group and the CWM alone group. Owing to the small sample size, this result would show that the effectiveness rates of acupoint injection combined with CWM for POP were better than using CWM alone. All in all, the pooled data showed that different treatment methods included in the TS (TK) principle combined with CWM were more effective than using CWM alone in improving effectiveness rates, with significant differences (RR = 1.28; 95% CI (1.23, 1.33); P<0.00001) (Figure 3(a)).Figure 3
(a) Effectiveness rates of different treatment methods included in the TS (TK) principle. (b) Effectiveness rates of different specific therapies included in TCM herbal medicine. (c) Effectiveness rates of different treatment periods. (d) BMD (lumbar spine) of different treatment periods. (e) BMD (proximal femur (femoral neck or total hip)) of different treatment periods. (f) Adverse effects. (g) TCM symptom integral. (h) VAS scores. Notes: the experimental group of Liu 2011 (2) was divided into 2 groups, respectively: Liu 2011 (2) and Liu 2011 (2)∗; the experimental group of Liu 2011 (3) was divided into 2 groups, respectively: Liu 2011 (3) and Liu 2011 (3)∗.
(a)(b)(c)(d)(e)(f)(g)(h)


## 3.3.2. Effectiveness Rates of Different Specific Therapies Included in TCM Herbal Medicine

There were 16 studies which reported effectiveness rates of different specific therapies included in TCM herbal medicine [21–23, 25, 27, 28, 30, 31, 33, 34, 36–41]. Five studies reported the effectiveness rates of bushen huoxue therapy [23, 36–39], three studies reported the effectiveness rates of bushen zhuanggu therapy [27, 31, 33], three studies reported the effectiveness rates of bushen jianpi therapy [22, 28, 30], and five studies reported the effectiveness rates of buyi ganshen therapy [21, 25, 34, 40, 41]. The heterogeneity among these studies was chi2 = 3.07, P=0.55; I2 = 0%, chi2 = 1.05, P=0.59; I2 = 0%, chi2 = 1.16, P=0.56; I2 = 0%, and chi2 = 3.02, P=0.55; I2 = 0%, respectively. Therefore, the fixed-effect model was applied to calculate the combined RR and 95% CI. After calculating, the combined RR and 95% CI was 1.18 (1.11, 1.24); P<0.00001, 1.36 (1.21, 1.53); P<0.00001, 1.34 (1.15, 1.57); P=0.0002, and 1.21 (1.11, 1.32); P<0.00001, respectively, indicating a statistically significant difference between the experimental group and the control group. This result suggests that bushen huoxue, bushen zhuanggu, bushen jianpi, and buyi ganshen TCM herbal medicine combined with CWM in the treatment of POP can significantly improve clinical efficacy when compared with using CWM alone. The combined data showed that different specific therapies included in TCM herbal medicine combined with CWM were more effective than using CWM alone in improving effectiveness rates, with significant differences (RR = 1.23; 95% CI (1.18, 1.29); P<0.00001) (Figure 3(b)).


## 3.3.3. Effectiveness Rates of Different Treatment Periods

Twenty-three literature studies reported effectiveness rates of different treatment periods [21–23, 26–28, 30, 31, 33, 34, 37–42, 44, 45, 47–50, 53]. Eleven literature studies reported treatment periods of less than 3 months [23, 27, 28, 37, 38, 41, 44, 45, 48–50]. However, there was high statistical heterogeneity among studies (chi2 = 22.88, P=0.01; I2 = 56%). A sensitivity analysis was performed to identify the source of heterogeneity. By removing one trial [38], no heterogeneity was detected (chi2 = 4.88, P=0.84; I2 = 0%). We confirmed the accuracy of the data without publication bias after contacting the author. So, we adopted a random-effect model to calculate the combined RR and 95% CI as 1.35 (1.27, 1.43), P<0.00001, indicating a statistically significant difference between the TS (TK) principle combined with the CWM group and the CWM alone group. It is suggested that using the TS (TK) principle combined with CWM for POP was better than using CWM alone in improving effectiveness rates when the treatment periods were less than 3 months. Twelve literature studies reported treatment periods of three to six months [21, 22, 25, 30, 31, 34, 39, 40, 42, 44, 47, 53]. There was no statistical heterogeneity among studies (chi2 = 7.92, P=0.85; I2 = 0%). Therefore, the fixed-effect model was applied to calculate the combined RR and 95% CI as 1.25 (1.18, 1.32), P<0.00001, indicating a statistically significant difference between the TS (TK) principle combined with the CWM group and the CWM alone group. It is suggested that using the TS (TK) principle combined with CWM for POP was better than using CWM alone in improving effectiveness rates when the treatment periods were three to six months. The pooled data showed that different treatment periods combined with CWM were more effective than using CWM alone in improving effectiveness rates, with significant differences (RR = 1.29; 95% CI (1.24, 1.35); P<0.00001) (Figure 3(c)).


## 3.3.4. BMD (Lumbar Spine) of Different Treatment Periods

Twenty-one studies reported BMD (lumbar spine) of different treatment periods [20, 21, 24, 25, 27, 29, 30, 32, 34, 35, 37–40, 42, 46, 48–50, 53, 54]. There were 8 studies which reported BMD (lumbar spine) of less than 3 months [27, 29, 37, 38, 48–50, 54], and 11 studies reported BMD (lumbar spine) of three to six months [21, 25, 30, 32, 34, 35, 39, 40, 42, 46, 53]. However, we detected high statistical heterogeneity among studies, chi2 = 40.14, P<0.00001; I2 = 83% and chi2 = 69.18, P<0.00001; I2 = 83%. The source of heterogeneity may be related to different treatment methods. Therefore, we adopted the random-effect model, and meta-analysis showed that there was a significant difference between the experimental and control groups (SMD = 0.83; 95% CI (0.52, 1.15); P<0.00001 and SMD = 0.56; 95% CI (0.27, 0.85); P<0.00001). It is suggested that using the TS (TK) principle combined with CWM less than three months or three to six months can both improve the BMD of the lumbar spine and is better than using CWM alone. Two studies reported BMD (lumbar spine) of more than six months [20, 24], and there was high statistical heterogeneity among studies (chi2 = 49.53, P<0.00001; I2 = 98%). We adopted the random-effect model, and meta-analysis showed that there was no significant difference between the experimental and control groups (SMD = 1.36; 95% CI (−1.33, 4.0); P=0.32). In general, the meta-analysis showed that different treatment periods combined with CWM were more effective than using CWM alone in improving the BMD of the lumbar spine, with significant differences (SMD = 0.71; 95% CI (0.47, 0.95); P<0.00001) (Figure 3(d)).


## 3.3.5. BMD (Proximal Femur (Femoral Neck or Total Hip)) of Different Treatment Periods

There were 15 studies which reported BMD (proximal femur (femoral neck or total hip)) of different treatment periods [19, 20, 24, 27, 30, 32, 34, 35, 37, 39, 42, 46, 51–53]. Two studies reported BMD (proximal femur (femoral neck or total hip)) of less than 3 months [27, 37]. High statistical heterogeneity among studies was detected (chi2 = 10.41, P=0.001; I2 = 90%); therefore, we adopted the random-effect model, and meta-analysis showed that there was no significant difference between the experimental and control groups (SMD = 0.53; 95% CI (−0.30, 1.36); P=0.21). Ten studies reported BMD (proximal femur (femoral neck or total hip)) of three to six months [30, 32, 34, 35, 39, 42, 46, 51–53]. There was high statistical heterogeneity among studies (chi2 = 52.61, P<0.00001; I2 = 83%). We performed sensitivity analysis by removing one trial [35], and low heterogeneity was detected (chi2 = 11.68, P=0.17; I2 = 32%). The source of heterogeneity may be related to different treatment methods. So, a random-effect model was adopted. The results showed that using the TS (TK) principle combined with CWM three to six months can improve the BMD of the proximal femur (femoral neck or total hip) and was better than using CWM alone (SMD = 0.69; 95% CI (0.34, 1.04); P<0.00001). Three studies reported BMD of more than six months, and these showed that there was high heterogeneity (chi2 = 135.92, P<0.00001; I2 = 99%) [19, 20, 24]. By removing one study [20], no heterogeneity was detected. The high heterogeneity may result from different treatment methods adopted by these studies. Thus, a random-effect model was adopted, and the results showed that there was no significant difference between the experimental and control groups (SMD = 2.06; 95% CI (0.36, 4.49); P=0.10). The combined data showed that different treatment periods combined with CWM were more effective than using CWM alone in improving the BMD of the proximal femur (femoral neck or total hip), with significant differences (SMD = 0.94; 95% CI (0.49, 1.38); P<0.00001) (Figure 3(e)).


## 3.3.6. Adverse Effects

Eleven studies reported adverse effects [19–21, 30, 33, 34, 36, 37, 39, 41, 53], and there was no statistical heterogeneity among studies (chi2 = 4.07, P=0.54; I2 = 0%). Hence, the fixed-effect model was applied to calculate the combined RR and 95% CI as 0.99 (0.65, 1.51), P=0.97, indicating no statistically significant difference between the experimental group and the control group. This result suggests that the TS (TK) principle combined with CWM or using CWM alone in the treatment of POP are both safe. Besides, the common adverse effects in the experimental group were gastrointestinal complaints, liver enzyme abnormal, hypertension, joint pain, stomach discomfort, nausea, vomiting, headache, musculoskeletal pain, etc. The adverse effects in the control group included gastrointestinal complaints, liver enzyme abnormal, hypertension, nausea, and vomiting (Figure 3(f)).


## 3.3.7. TCM Symptom Integral

The TCM symptom integral was established according to theClinical Research Guidance of New Chinese Herbal Medicine [55]. Four studies reported TCM symptom integral [26, 40, 46, 54], and there was low statistical heterogeneity among studies (chi2 = 7.49, P=0.19; I2 = 33%). Therefore, the fixed-effect model was applied. The meta-analysis showed that there was a statistically significant difference between the experimental group and the control group (SMD = −1.23; 95% CI (−1.43, −1.02); P<0.00001). This result suggests that the TS (TK) principle combined with CWM in the treatment of POP can significantly improve TCM symptom integral when compared with using CWM alone (Figure 3(g)).


## 3.3.8. VAS Scores

There were 10 studies which reported VAS scores [21, 23, 25, 31, 34, 40, 43, 48–50]. The result showed that there was high statistical heterogeneity among studies (chi2 = 733.80, P<0.00001; I2 = 99%), so we adopted a random-effect model. The combined data showed that there was a statistically significant difference between the experimental group and the control group (SMD = −3.88; 95% CI (−5.29, −2.46); P<0.00001). This result suggests that the TS (TK) principle combined with CWM in the treatment of POP was more effective than using CWM alone in improving VAS scores (Figure 3(h)).


## 3.3.9. Publication Bias

The funnel plots were generated for studies with data on the effectiveness rates of different treatment methods included in the TS (TK) principle. The results showed that most of the points in the funnel plots were symmetrical. However, two points were outside the 95% CIs, which indicates that there may have been publication bias in our studies and that might influence the results of our analysis, as can be seen in Figure4.Figure 4
Funnel plot of effectiveness rates of different treatment methods included in the TS (TK) principle.


## 3.3.10. Quality of Evidence

There were 8 results for levels of evidence in our study. The detailed GRADE evidence profile of results is shown in Figure5.Figure 5
GRADE evidence profile.


## 4. Discussion

### 4.1. Summary of Main Results

There were 36 included RCTs with 3617 participants in our research. Even though most of the trials had small sample sizes and poor methodological quality, our meta-analysis reached the following results: (1) analysis of the pooled data showed a consistently superior effect of the TS (TK) principle combined with CWM in terms of total effectiveness rates, BMD of the lumbar spine and proximal femur (femoral neck or total hip), TCM symptom integral, and VAS scores when compared to using CWM alone; (2) in terms of adverse effects, the same safety was obtained for the TS (TK) principle combined with CWM or using CWM alone for POP; (3) different treatment methods included in the TS (TK) principle combined with CWM were more effective than using CWM alone in improving effectiveness rates. It should be noted that since the sample size of acupoint injection effectiveness rates was small, the combined RR and 95% CI was reported from the original study, not from the meta-analysis results; (4) in respect of TCM herbal medicine, different specific therapies combined with CWM for POP were more effective than using CWM alone; (5) compared with using CWM alone, the TS (TK) principle combined with CWM was more effective for POP in the aspect of different treatment periods; (6) in the three-to six-month treatment period, the TS (TK) principle combined with CWM for POP in terms of BMD of the lumbar spine and proximal femur (femoral neck or total hip) was better than using CWM alone; (7) according to the guideline of GRADE, the effectiveness rates of different treatment methods included in the TS (TK) principle, effectiveness rates of different specific therapies included in TCM herbal medicine, effectiveness rates of different treatment periods, BMD (lumbar spine) of different treatment periods, BMD (proximal femur (femoral neck or total hip)) of different treatment periods, TCM symptom integral, and VAS scores were moderate level of evidence. The adverse effects were low of evidence.


### 4.2. Analysis of TS (TK) Principle

TCM has been used in a range of medical management and health interventions in China and any other Asian countries for over 2500 years. POP patients are usually seeking TCM treatment, when the therapeutic effect of CWM is unsatisfactory. According to TCM theory, the establishment of a therapeutic principle is based on TCM syndromes, not symptoms. The clinical diagnosis of the TCM syndrome relies on the gathering of clinical information through inspection, auscultation and olfaction, inquiry, and palpation [56]. For POP, the fundamental physiopathological changes of the bone depend on whether Shen (kidney) essence is sufficient or not. Therefore, the TS (TK) principle is the key point to prevent and treat Shen (kidney)-deficiency syndrome of POP [57–60]. On the one hand, the effective mechanisms of pharmaceutical treatment included in the TS (TK) principle on POP have been demonstrated in the voluminous literature. Icariin (ICA), similar to estrogen, has a definite antiosteoporotic effect [61, 62]. Besides, oleanolic acid (OA) and psoralen have been reported to prevent bone loss by inhibiting osteoclast formation [63–65]. On the other hand, in respect of nonpharmaceutical treatment included in the TS (TK) principle, experiments have demonstrated that acupuncture could alleviate osteoporosis by regulating the expression of members in OPG/RANKL, Wnt/β-catenin, and MAPK pathways [66]. Acupoint catgut embedding could regulate the hypothalamic-pituitary-ovarian axis to raise the serum E2 level which would be significant in preventing osteoporosis [67]. Even experiments have shown that acupoint catgut embedding ameliorated the ovariectomization- (OVX-) caused metabonomic changes more effectively than hormone replacement therapy (HRT) with nilestriol [68]. Also, nonpharmaceutical treatment could alleviate related symptoms of osteoporosis and improve the quality of life [43]. Therefore, the TS (TK) principle would be a promising approach for POP, and it can not only improve physiological and biochemical indicators but also alleviate the TCM syndromes [16].


### 4.3. Limitations of Research

However, some limitations in our meta-analysis should be mentioned. (1) Although all of our included studies were RCTs, the methodological quality of them was generally improvable. Most of them failed to describe the blinding methods in detail, allocation, and concealment methods. (2) Among 36 studies, only 8 studies reported follow-up. The longest follow-up period was 120 months, and no further follow-up data were collected. The long-term effect of the TS (TK) principle for POP should be further studied. (3) For POP, fracture incidence should be the most patient-important outcomes. However, no fracture incidence data were collected in our studies. It is necessary to focus on fracture incidence as a patient-important outcome in further studies. (4) The studies included in this analysis were insufficient, especially in terms of subgroup analysis. Thus, potential publication bias probably exists. (5) The high heterogeneity among studies may be related to the different treatment methods, treatment periods, and even the skill level of the practitioners. It is a common problem in the research of TCM therapy. (6) The study for different specific therapies of TCM herbal medicine was insufficient, and further data mining should be carried out.


## 4.1. Summary of Main Results

There were 36 included RCTs with 3617 participants in our research. Even though most of the trials had small sample sizes and poor methodological quality, our meta-analysis reached the following results: (1) analysis of the pooled data showed a consistently superior effect of the TS (TK) principle combined with CWM in terms of total effectiveness rates, BMD of the lumbar spine and proximal femur (femoral neck or total hip), TCM symptom integral, and VAS scores when compared to using CWM alone; (2) in terms of adverse effects, the same safety was obtained for the TS (TK) principle combined with CWM or using CWM alone for POP; (3) different treatment methods included in the TS (TK) principle combined with CWM were more effective than using CWM alone in improving effectiveness rates. It should be noted that since the sample size of acupoint injection effectiveness rates was small, the combined RR and 95% CI was reported from the original study, not from the meta-analysis results; (4) in respect of TCM herbal medicine, different specific therapies combined with CWM for POP were more effective than using CWM alone; (5) compared with using CWM alone, the TS (TK) principle combined with CWM was more effective for POP in the aspect of different treatment periods; (6) in the three-to six-month treatment period, the TS (TK) principle combined with CWM for POP in terms of BMD of the lumbar spine and proximal femur (femoral neck or total hip) was better than using CWM alone; (7) according to the guideline of GRADE, the effectiveness rates of different treatment methods included in the TS (TK) principle, effectiveness rates of different specific therapies included in TCM herbal medicine, effectiveness rates of different treatment periods, BMD (lumbar spine) of different treatment periods, BMD (proximal femur (femoral neck or total hip)) of different treatment periods, TCM symptom integral, and VAS scores were moderate level of evidence. The adverse effects were low of evidence.


## 4.2. Analysis of TS (TK) Principle

TCM has been used in a range of medical management and health interventions in China and any other Asian countries for over 2500 years. POP patients are usually seeking TCM treatment, when the therapeutic effect of CWM is unsatisfactory. According to TCM theory, the establishment of a therapeutic principle is based on TCM syndromes, not symptoms. The clinical diagnosis of the TCM syndrome relies on the gathering of clinical information through inspection, auscultation and olfaction, inquiry, and palpation [56]. For POP, the fundamental physiopathological changes of the bone depend on whether Shen (kidney) essence is sufficient or not. Therefore, the TS (TK) principle is the key point to prevent and treat Shen (kidney)-deficiency syndrome of POP [57–60]. On the one hand, the effective mechanisms of pharmaceutical treatment included in the TS (TK) principle on POP have been demonstrated in the voluminous literature. Icariin (ICA), similar to estrogen, has a definite antiosteoporotic effect [61, 62]. Besides, oleanolic acid (OA) and psoralen have been reported to prevent bone loss by inhibiting osteoclast formation [63–65]. On the other hand, in respect of nonpharmaceutical treatment included in the TS (TK) principle, experiments have demonstrated that acupuncture could alleviate osteoporosis by regulating the expression of members in OPG/RANKL, Wnt/β-catenin, and MAPK pathways [66]. Acupoint catgut embedding could regulate the hypothalamic-pituitary-ovarian axis to raise the serum E2 level which would be significant in preventing osteoporosis [67]. Even experiments have shown that acupoint catgut embedding ameliorated the ovariectomization- (OVX-) caused metabonomic changes more effectively than hormone replacement therapy (HRT) with nilestriol [68]. Also, nonpharmaceutical treatment could alleviate related symptoms of osteoporosis and improve the quality of life [43]. Therefore, the TS (TK) principle would be a promising approach for POP, and it can not only improve physiological and biochemical indicators but also alleviate the TCM syndromes [16].


## 4.3. Limitations of Research

However, some limitations in our meta-analysis should be mentioned. (1) Although all of our included studies were RCTs, the methodological quality of them was generally improvable. Most of them failed to describe the blinding methods in detail, allocation, and concealment methods. (2) Among 36 studies, only 8 studies reported follow-up. The longest follow-up period was 120 months, and no further follow-up data were collected. The long-term effect of the TS (TK) principle for POP should be further studied. (3) For POP, fracture incidence should be the most patient-important outcomes. However, no fracture incidence data were collected in our studies. It is necessary to focus on fracture incidence as a patient-important outcome in further studies. (4) The studies included in this analysis were insufficient, especially in terms of subgroup analysis. Thus, potential publication bias probably exists. (5) The high heterogeneity among studies may be related to the different treatment methods, treatment periods, and even the skill level of the practitioners. It is a common problem in the research of TCM therapy. (6) The study for different specific therapies of TCM herbal medicine was insufficient, and further data mining should be carried out.


## 5. Conclusion

In summary, our meta-analysis suggests that using the TS (TK) principle combined with CWM for POP is effective and safe. However, the limitation in the quality and quantity of the included RCTs might weaken the overall reliability of this conclusion. Therefore, large-volume, well-designed RCTs with extensive follow-up are awaited to confirm and update the findings of this analysis.



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*Source: 5687421-2020-10-06.xml*