LI Kai-ming, JIA Yi-xuan, SUN Jian-feng, SHEN Yang-yong, REN Gui-ju, CAI Tongchuan, ZHANG Qing, SUN Shu-chun ,CHONG Hui?

1. Xiyuan Hospital of China Academy of Chinese Medical Sciences,Beijing 100091,China

2. Wangjing Hospital of China Academy of Chinese Medical Sciences,Beijing 100102,China

Keywords:

ABSTRACT Objective: To systematically evaluate the long-term efficacy of Bushen Huoxue Decoction combined with vertebroplasty (PVP or PKP) in the treatment of osteoporotic vertebral compression fractures (OVCF), in order to provide evidence-based reference for clinical application.Methods: To ensure the novelty of research data, a computer search was conducted between 2017 and February 2023 to publicly publish all randomized controlled studies and clinical trials at home and abroad on the treatment of OVCF with Bushen Huoxue Decoction combined with vertebroplasty published in CNKI, Wanfang, Vip, PubMed, CBM,and Cochrane libraries.Two researchers independently conducted literature screening and data extraction, evaluated the quality of randomized controlled trials included one by one according to the Cochrane collaboration network standards, and conducted a meta statistical analysis using RevMan5.3 for studies that met the inclusion criteria.Results: A total of 684 patients were included in 7 randomized controlled trials, including 342 patients in the observation group and 342 patients in the control group, with a ratio of 1:1; The meta-analysis results showed that in the observation group, the overall effective rate [RR=1.30, 95% CI (1.14,1.47), P＜0.001], visual analog pain (VAS) score [SMD=1.19, 95% CI (0.77, 1.61), P＜0.0001],bone mineral density score [SMD=1.09, 95% CI (0.15, 2.04), P=0.02], COQOL score [SMD=0.99,95%CI(0.68,1.30), P＜0.00001], OPG score [SMD=0.48, 95% CI (0.18, 0.77), P=0.002]The RANKL score [SMD=1.33, 95% CI (1.00, 1.65), P＜0.0001] was significantly superior to the control group, with statistically significant differences.There was no significant difference in the Oswestry Disability Index (ODI) score [SMD=0.27, 95% CI (-0.03, 0.57), P=0.08],Cobb score [SMD=1.52, 95% CI (-1.05, 4.09), P=0.25], and vertebral height score [SMD=0.43,95% CI (-0.14, 1.01), P=0.14].Conclusion: The results show that Bushen Huoxue Decoction combined with vertebroplasty has significant advantages in improving bone mineral density and alleviating pain in patients after OVCF, which is significantly superior to using OVCF alone.

1.Introduction

Osteoporosis (OP) is a metabolic bone disease caused by a decrease in bone density, which increases the fragility of bones and leads to fractures, resulting in many complications such as pain, flattening, deformation, and fracture[1].Moreover, due to the limb disability caused by fractures, patients have limited mobility,long-term bed rest, lung infections, bedsores, etc., especially for elderly patients, the mortality rate greatly increases[2].Osteoporotic vertebral compression fracture (OVCF), as one of the most common complications of OP, has an increasing incidence rate year by year, with an obvious trend of youth[3].In recent years, with the continuous progress of medical technology, minimally invasive surgeries such as percutaneous vertebroplasty and kyphoplasty have emerged.The treatment effect for this type of fracture is significant,which can effectively restore the height of the compressed vertebral body, quickly alleviate back pain in the short term, improve spinal biological function, and allow patients to quickly move to the ground, reducing complications caused by long-term bed rest, High acceptance level[4].However, follow-up found that the incidence of recurrent fractures in the adjacent vertebral bodies of patients is relatively high within a period of time after surgery, and osteoporosis in patients is still worsening.Therefore, surgery alone cannot effectively reduce risk factors such as vertebral fractures[5].Osteoporosis belongs to the category of “bone obstruction” and“bone flaccidity” in Tradit Chin Med.Its root cause is insufficient kidney essence, deficiency of vital energy, stasis blocking meridians,and the inability of qi, blood, and body fluids to nourish the muscles and bones, which can easily become loose and fragile.This emphasizes the importance of tonifying the kidney and promoting blood circulation in the treatment of osteoporosis[6].At present, a large number of clinical literature has reported the clinical research of using Bushen Huoxue Tang to treat osteoporosis, especially in the anti osteoporosis treatment after OVCF surgery.However, due to the small sample size and outdated literature in some clinical studies, the reference value of the conclusions obtained is limited and insufficient to provide effective guidance for clinical applications.Therefore,this study systematically analyzed and evaluated relevant literature in the past five years, further expanded observation indicators, and evaluated their effectiveness, providing evidence-based basis for the clinical application of Bushen Huoxue Tang in treating osteoporosis after OVCF surgery.

2.Materials and methods

2.1 Criteria for inclusion and exclusion of literature

2.1.1 Inclusion Criteria

Randomized controlled trial (RCT) on the treatment of OP with modified Bushen Huoxue Tang, published domestically and internationally; The study subjects were OVCF patients, and the treatment plan control group was PKP or PVP; The observation group consisted of PKP or PVP combined with Bushen Huoxue Tang with modifications.

2.1.2 Exclusion Criteria

No RCT; The setting of treatment plans is not standardized;Repeated publications; Does not comply with statistical design principles; Data with obvious errors and incomplete relevant information.

2.2 Outcome indicators

Main outcome indicators: total effective rate, visual analogue pain (VAS) score, Oswestry Dysfunction Index (ODI) score, and bone mineral density (BMD) score; Secondary outcome indicators:Chinese Osteoporosis quality of life short form questionnaire(COQOL) score, serum osteoprotegerin (OPG) score, nuclear factor κ B receptor activator of nuclear factor kappa- Β Ligand, RANKL)score, Cobb score, and vertebral height score.

2.3 literature search

The RCT study on the treatment of OVCF with Bushen Huoxue Tang combined with vertebroplasty was conducted through computer retrieval of Chinese databases such as CNKI and Wanfang, as well as English databases such as PubMed and Cochrane.The search language is unlimited, and to ensure the reliability and novelty of the research data, the search time is from January 2017 to February 2023.Chinese search term: tonifying the kidney and promoting blood circulation; osteoporosis; Vertebroplasty, English key word: Bushen Huoxue; osteoporosis; PKP; PVP; osteoporotic vertebral compression fracture; OVCF.

2.4 Literature screening and data extraction

Two evaluators will classify and screen according to relevant standards.In case of disagreement, a third party will discuss and negotiate together.Formulate standardized data tables, extract and summarize the basic information and observation contents of research data, such as research type, number of cases, outcome indicators, etc.If necessary information is lacking, contact the lead author as far as possible to obtain it.

2.5 Quality evaluation of literature methodology

According to the relevant evaluation standards of Cochrane Collaboration Network, low quality: 1-3 points, high quality: 4-7 points.Specific indicator score: correct (2 points); Unclear (1 point);Incorrect (0 point).

2.6 Statistical analysis methods

RevMan 5.3 software was used for data statistical analysis.Firstly,heterogeneity analysis was conducted.If I2＜50%, there was no statistical heterogeneity or the heterogeneity was small.Therefore, a fixed effects model was used for statistical analysis; If I2＞50%, there is heterogeneity in the study, so a random effects model is selected for data analysis; The total effective rate is measured by RR as the effect quantity; Use mean difference (MD) for measurement data such as VAS, ODI, BMD, and COQOL.If the statistical methods are inconsistent, use SMD to represent them; The final 95% confidence interval (CI) was set, and if P＜0.05, it indicates that there is no significant difference in the results.

3.Results

3.1 Literature retrieval and screening process

Preliminary screening and retrieval of 1109 relevant literature were conducted, and a total of 7 articles[7-13] were included in the RCT after removing duplicate literature, reading questions, preliminary screening of abstracts, and reading the entire text, as shown in Figure 1.

Fig 1 Flow chart of literature search and screening

3.3 Meta analysis results

3.3.1 Total effective rate

Three articles[8,10,12] compared the total effective rate after treatment.There is no heterogeneity among the studies (I2=0%), so a fixed effects model is used.The total effective rate of the observation group was better than that of the control group [RR=1.30, 95% CI(1.14, 1.47), P＜0.001], as shown in Figure 3.

3.3.2 VAS scores

A total of 6 articles[8-13] observed the VAS score, and there was heterogeneity among the study groups (I2= 82%), analyzed using a random effects model.There was a statistically significant difference in VAS scores between the two groups after treatment [SMD=1.19,95% CI (0.77, 1.61), P＜0.0001], as shown in Figure 4.

3.3.3 BMD scores

Five articles[8,9,11-13] reported the bone density of the vertebral body after treatment, and there was heterogeneity among the study groups (I2= 96%), analyzed using a random effects model.The bonedensity of the observation group was higher than that of the control group [SMD=1.09, 95% CI (0.15, 2.04), P=0.02], as shown in Figure 5.

Tab 1 The basic characteristics of the study

Tab 2 The literature quality evaluation

Fig 2 Risk of bias assessment of the study

3.3.4 ODI scores

Two articles[8,9] compared the ODI scores after treatment.Firstly,a heterogeneity test was conducted, and it was found that there was no heterogeneity between the two groups (I2=0%), so a fixed effects model was used.There was no significant difference in the ODI scores between the two groups after treatment [SMD=0.27, 95% CI(-0.03, 0.57), P=0.08], as shown in Figure 6.

Fig 3 Overall efficiency after treatment

Fig 4 VAS score after treatment

Fig 5 BMD score after treatment

Fig 6 ODI score after treatment

3.3.5 COQOL scores

Two articles[7,9] compared the COQOL scores after treatment.The heterogeneity test showed no significant heterogeneity (I2=47%), so a fixed effects model was used.The changes in COQOL scores after two treatment methods showed significant significance [SMD=0.99,95% CI (0.68, 1.30), P＜0.0001], as shown in Figure 7.

3.3.6 OPG scores

Two articles[7,9] compared the OPG scores after treatment.The study showed that there was no heterogeneity between the two groups (I2=0%), so a fixed effect model was used.After treatment,the OPG score of the observation group was significantly better than that of the control group [SMD=0.48, 95% CI (0.18, 0.77), P＜0.02],as shown in Figure 8.

3.3.7 RANKL scores

Two articles[8,13,16,18-20,23,27] compared the RANKL scores after treatment.The heterogeneity test showed (I2=0%), so a fixed effect model was used.The difference in RANKL scores between the two groups after treatment was statistically significant [SMD=1.58, 95%CI (1.05, 2.10), P＜0.0001], as shown in Figure 9.

3.3.8 Cobb scores

Four articles[8,10,11,13] compared the Cobb scores after treatment.The heterogeneity test showed significant heterogeneity (I2=94%),so a random effects model was used.There was no significant difference in improving Cobb between the two groups [SMD=1.52,95% CI (-1.05, 4.09), P=0.25], as shown in Figure 10.

Fig 7 COQOL score after treatment

Fig 8 OPG score after treatment

Fig 9 RANKL score after treatment

Fig 10 Cobb score after treatment

3.3.9 Vertebral height scores

Three articles[7,11,13] compared the vertebral height scores after treatment.Heterogeneity testing indicates significant heterogeneity between the two groups (I2=85%), so a random effects model was used.There was no significant difference in vertebral height score between the two methods of treatment [SMD=0.43, 95% CI (-0.14,1.01), P=0.14], as shown in Figure 11.

Fig 11 The vertebral height score

4.Discussion

In recent years, OVCF, as one of the common diseases in clinical orthopaedics, its incidence rate has been increasing year by year.The main reason is that the aging degree is getting worse, bad life and diet rules cause progressive changes in body functions, significant calcium loss in the body, accelerate the process of bone absorption,and ultimately lead to osteoporosis.After a vertebral fracture occurs,the mechanical structure of the bone changes, causing compression and deformation of the vertebral body, which further exacerbates the process of adjacent vertebral fractures, causing great distress to the physical and mental health and daily living ability of elderly patients[14-15].Therefore, how to effectively prevent fractures and actively treat osteoporosis has become the primary problem currently faced.Percutaneous vertebroplasty, as a new technology for the treatment of OVCF, has been widely used in clinical practice.It can quickly alleviate the pain caused by fractures, improve patients’ quality of life, and accelerate the recovery process.However, in actively treating primary diseases, improving bone density, and residual pain,OVCF has certain limitations, causing significant distress to many elderly patients and worrying about the occurrence of secondary fractures.Osteoporosis belongs to the category of “bone blockage”and “bone flaccidity” in Tradit Chin Med.The Inner Classic states:“The waist is the palace of the kidneys, which store essence,regulate bones, and nourish marrow.Kidney essence deficiency leads to passive myelination and bone loss of nourishment.Kidney is the foundation of congenital diseases.Kidney deficiency leads to disorder of visceral and qi mechanisms, loss of qi and blood circulation, stagnation of blood stasis, and exacerbation of bone dysfunction.Therefore, kidney deficiency and blood stasis may be the fundamental cause of osteoporosis, and clinical treatment should mainly focus on tonifying the kidney, filling the lean marrow,promoting blood circulation, resolving blood stasis, and alleviating pain[16-17].

At present, a large number of clinical scholars have adopted the method of tonifying the kidney, activating blood circulation, and unblocking collaterals to treat primary osteoporosis with kidney deficiency and blood stasis syndrome, which has a significant therapeutic effect.It can not only improve the bone density value of patients, reduce bone loss, but also effectively alleviate back and waist muscle pain, with a significant long-term effect.Modern medical research has shown that Tradit Chin Med for tonifying the kidney and promoting blood circulation can effectively reduce the expression level of inflammatory factors in serum, regulate bone metabolism imbalance, increase bone mineralization, improve bone, and have a certain therapeutic effect on postmenopausal osteoporosis[18].Liu Kai et al[19] observed the effect of Bushen Huoxue Formula on IL-6 in serum and proximal femur bone density of ovariectomized rats, and found that this formula can effectively reduce serum IL-6 levels and significantly increase bone density values in ovariectomized rats.In order to further systematically evaluate the therapeutic effect of Bushen Huoxue Tang on osteoporosis, a total of 7 randomized controlled trial articles were included in this study.Through meta-analysis, the observation group was significantly better than the control group in terms of overall effective rate, visual simulated pain (VAS) score, bone density score, COQOL score, OPG score, RANKL score, etc.(P＜0.05).The results indicate that Bushen Huoxue Tang can effectively improve the clinical symptoms of patients after OVCF surgery, increase bone density, improve bone metabolism levels, and improve quality of life.It can be seen that Bushen Huoxue Tang can be used for clinical treatment of osteoporosis.Further validated the advantages of Tradit Chin Med in the prevention and treatment of osteoporosis and vertebral fractures.Its auxiliary percutaneous vertebroplasty has a significant therapeutic effect on OVCF, and also provides a practical and reliable evidence-based basis for the later clinical application of Bushen Huoxue Tang.

At the same time, there are still many limitations in this study,such as the lack of inclusion of foreign literature, a small total number of literature, and the lack of clear explanation of specific blinding methods in most literature, which may result in some bias in the results and incorrect expression in data analysis.In addition,there is a problem with a single outcome indicator in the selected literature for analysis, which fails to select internationally or industry recognized evaluation indicators.Therefore, in order to objectively evaluate the authenticity and reliability of clinical research results,we will continue to expand the sample size, extend the followup period, include high-quality research, follow the CONSORT standard, further verify its efficacy, and provide high-level evidencebased basis for the clinical application of Bushen Huoxue Tang.

Author’s contribution

Li Kaiming: As the design executor of this study, completed literature screening, data collection and analysis, and wrote the first draft of the paper; Chonghui and Sun Jianfeng: Overall guidance for the design of research plans; Sun Shuchun and Shen Yangyong:Criticism and correction of the content of the article; Jia Yixuan:Conduct research screening on reading topics and abstracts; Zhang Qing: Participated in scheme design, data analysis, and correction of paper content; Ren Guiju: Participate in the process of data collection and analysis; Cai Tongchuan: Participate in data collection and input, participate in literature review, etc.

All authors declare that there is no conflict of interest relationship.