Randomized Controlled Trials (RCTs) of Gukang Capsule in POP treatment were searched in PubMed, Web of science, Cochrane Library, China National Knowledge Infrastructure, Chongqing VIP Information, and Wanfang databases. The retrieval time was from the databases’ inception to 30 September 2023. We adopted the retrieval strategy of combined subject words and free words. The keywords included: ‘Gukang Capsule’ ‘Gukang Jiaonang’ ‘Osteoporosis’ ‘Osteoporosis, Postmenopausal’ ‘Senile Osteoporosis’ and ‘Osteoporotic Fracture (OPF)’. The search process is detailed in the Supplementary Material S5.

Literature search and screening were independently performed by two reviewers (Zhenpu Wei and Zhiqiang Wang). Specifically, they extracted basic information, intervention measures, outcomes, and other relevant data. A third reviewer (Yanping Lin) was consulted for any inconsistencies.

Two reviewers (Zhenpu Wei and Yunmei Huang) performed the biased risk assessment using the bias risk assessment tool recommended in the Cochrane Manual (Zhu et al., 2018). The details assessed were as follows: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other relevant aspects. Each item was tagged as high risk, low risk, or unclear.

Clinical data were analyzed using Review Manager 5.3. Count data were evaluated using Relative Risk (RR) and 95% Confidence Interval (CI). Measurement data were analysed using the Standardised Mean Difference (SMD) and 95%CI (Huang et al., 2022). We further explored heterogeneity between the included studies. Studies were considered to have low variability if two conditions were met: 1) the I² < 50%, and 2) the p-value >0.05. In cases with low variability, a fixed effects model was used to analyze the data. On the other hand, studies were considered to have high variability if either the I² statistic was 50% or greater, or the p-value was greater than 0.05 (indicating a lack of statistical significance). When high variability was found, a random effects model was employed for data analysis (Cordero and Dans, 2020). Subgroup analyses were performed based on whether POP and OPF were combined. Sensitivity and bias analyses were performed using Stata 12.0 (Xu et al., 2009).

Our initial search identified 180 articles. After removing duplicates (62 articles), we screened the abstracts of the remaining 118 articles. This process excluded 73 articles, leaving 45 full-text articles for further evaluation. Following a thorough review, 19 articles were ultimately determined to meet the inclusion criteria for this study. (Wang et al., 2014; Wang et al., 2015; Yu et al., 2015; Shen, 2016; Yan, 2016; Chen, 2018; Li, 2018; Li et al., 2019; Ye, 2019; Zhao et al., 2019; Liao et al., 2021; Yue and Huang, 2021; Zhou et al., 2021; Cai et al., 2022; Li et al., 2022; Xu, 2022; He et al., 2023; Sun and Xie, 2023; Tian, 2023) (Figure 1).

Herein, 1804 POP patients (906 and 898 patients in the experimental and control groups, respectively) were included. Two studies (Chen, 2018; Ye, 2019) included POP patients, five studies (Li, 2018; Zhao et al., 2019; Li et al., 2022; Xu, 2022; Tian, 2023) included SOP patients, three studies (Wang et al., 2014; Yu et al., 2015; Liao et al., 2021) included PMOP patients, and nine studies (Wang et al., 2015; Shen, 2016; Yan, 2016; Li et al., 2019; Yue and Huang, 2021; Zhou et al., 2021; Cai et al., 2022; He et al., 2023; Sun and Xie, 2023) included POP+OPF patients. Except for one study (Cai et al., 2022), which did not mention the drug source, the other 18 studies (Wang et al., 2014; Wang et al., 2015; Yu et al., 2015; Shen, 2016; Yan, 2016; Chen, 2018; Li, 2018; Li et al., 2019; Ye, 2019; Zhao et al., 2019; Liao et al., 2021; Yue and Huang, 2021; Zhou et al., 2021; Li et al., 2022; Xu, 2022; He et al., 2023; Sun and Xie, 2023; Tian, 2023) mentioned that the Gukang Capsule used were produced by Guizhou Weikang Zifan Pharmaceutical Co., Ltd. (SINomatol: Z20025657) (Table 1).

Twelve studies (Yu et al., 2015; Shen, 2016; Yan, 2016; Chen, 2018; Li, 2018; Li et al., 2019; Yue and Huang, 2021; Cai et al., 2022; Li et al., 2022; Xu, 2022; Sun and Xie, 2023; Tian, 2023) were grouped based on the random number table method (low risk), one study (Liao et al., 2021) were grouped based on the modular arithmetic method (low risk), one study (Ye, 2019) were grouped based on treatment protocol (high risk), and one study (Zhou et al., 2021) were grouped based on single or even numbers (high risk). Four studies (Wang et al., 2014; Wang et al., 2015; Zhao et al., 2019; He et al., 2023) did not mention the specific randomized methods used (unclear). Allocation hiding (high risk) was not implemented in 19 studies (Wang et al., 2014; Wang et al., 2015; Yu et al., 2015; Shen, 2016; Yan, 2016; Chen, 2018; Li, 2018; Li et al., 2019; Ye, 2019; Zhao et al., 2019; Liao et al., 2021; Yue and Huang, 2021; Zhou et al., 2021; Cai et al., 2022; Li et al., 2022; Xu, 2022; He et al., 2023; Sun and Xie, 2023; Tian, 2023). None of the 19 studies reported whether they were blinded (unclear). All studies (Wang et al., 2014; Wang et al., 2015; Yu et al., 2015; Shen, 2016; Yan, 2016; Chen, 2018; Li, 2018; Li et al., 2019; Ye, 2019; Zhao et al., 2019; Liao et al., 2021; Yue and Huang, 2021; Zhou et al., 2021; Cai et al., 2022; Li et al., 2022; Xu, 2022; He et al., 2023; Sun and Xie, 2023; Tian, 2023) had complete data (low risk), no selective reporting of findings (low risk), and no other sources of bias (low risk) (Figure 2).

Sensitivity analysis was performed for each outcome by eliminating one study at a time and recombining the statistics. No significant change was observed in all outcomes, implying the stability of the study results (Figure 13).

Funnel plots are a graphical tool used to assess publication bias in a meta-analysis. They depict the relationship between the effect size (strength of the observed effect) of individual studies and their standard error (a measure of the study’s precision). In the absence of publication bias, the plot ideally resembles a symmetrical inverted funnel. Smaller studies, typically with higher standard errors, would be scattered at the bottom, while larger and more precise studies would cluster towards the top. Deviations from this symmetrical shape, particularly a narrower funnel at the bottom, can suggest publication bias. This bias occurs when studies with statistically non-significant results (those that do not show a strong effect) are less likely to be published, leading to an overestimation of the overall treatment effect (Hopp, 2015). The publication bias funnel plot was drawn using the total effective rate. The distribution of scattered points in each study was asymmetrical, implying potential publication bias (Figure 14A). Egger’s test is a statistical test used to quantify the funnel plot asymmetry and provide a more objective assessment of publication bias. A significant result from Egger’s test suggests the presence of publication bias (Hopp, 2015). The Egger’s test was used to quantify each outcome’s bias. According to the results, the P>|t|-values of serum BALP levels and serum TRACP-5b levels were <0.1, indicating potential publication bias. The P>|t|-values of the other outcomes were >0.1, implying no significant bias. Publication bias may be the result of concealing negative results. (Figure 14B). Since positive results are more likely to be published and cited, negative results are often overlooked or not readily available, which may lead to the bias of meta-analysis results.

Yang et al. (2018) explored the Gukang Capsule effects on the proliferation, differentiation, and mineralization of human osteoblast SaOS-2 cultured in vitro. The results showed that GC can promote osteoblast proliferation, differentiation, and mineralization. Furthermore, a literature search revealed that Gukang Capsule can be used in combination with calcium, vitamin D, bisphosphonates, or calcitonin in POP treatment. Overall, Gukang Capsule has been reported in several studies to exert a good curative effect in POP patients. However, the conclusions of these studies are often not evidence-based and unconvincing due to the influence of inconsistent treatment methods, and insufficient sample sizes. Herein, 19 RCTs (1804 patients) were reviewed to further elucidate Gukang Capsule efficacy in treating POP. Compared to the control group, treatment with Gukang Capsule resulted in several positive outcomes. These included increased BMD in the lumbar vertebrae, femoral head, and Ward’s triangle, improved quality of life, shortened healing time for OPFs, and a higher total effective rate. Furthermore, a meta-analysis of serum bone metabolism markers revealed that Gukang Capsule may regulate bone formation and resorption. This is evidenced by reductions in levels of bone ALP (BALP) and TRACP-5b, which are indicators of these processes.

The Standardization Office of the Chinese Society of Traditional Chinese Medicine systematically combed the clinical and basic research results of Gukang Capsule since its listing, and formed the ‘Expert Consensus on the clinical application of Gukang Capsule in the Treatment of Osteoporosis’ on the basis of full consideration of clinical research evidence and expert experience. This consensus statement outlines the recommended use of Gukang Capsule for treating OP. It defines the ideal patient characteristics, typical symptoms, and disease stages suitable for Gukang Capsule therapy. Moreover, it specifies the recommended dosage, treatment duration, potential interactions with other medications, and any necessary precautions for safe use. Furthermore, the statement clarifies when Gukang Capsule is contraindicated (Zhu et al., 2022). The consensus points out that Gukang capsule in the treatment of OP can improve the bone mineral density of patients (strongly recommendation), improve the level of bone turnover markers (β-CTX, PINP, N-MID-OT, 25(OH)D) and bone metabolism biochemical indicators (BGP, BALP, TRACP-5b) of patients (weak recommendation). Gukang capsule in the treatment of osteoporosis can relieve pain, improve dysfunction, improve patients’ quality of life (strongly recommended). When Gukang capsule is used in combination with other drugs, the therapeutic effect is more significant (strongly recommended) (Zhu et al., 2022).

An acute drug toxicity test and long-term drug experiment showed that Gukang Capsule did not pose an acute toxicity risk or delay drug toxicity (Zhu et al., 2022). Additionally, a study was conducted on the effect of Gukang Capsule on drug transporter protein expression in rat liver. The results showed that Gukang Capsule could alter the expression of liver drug transporter proteins, including OATP1B1, OCT1, MRP1, MRP2, BCRP, and PGP, in a dose-dependent manner (Li et al., 2021). Combining Gukang Capsule with certain medications, particularly those with a narrow therapeutic window, may lead to drug interactions. These interactions may occur through transporter proteins and could affect how the medications are absorbed and distributed in the body. Zhu et al. (Zhu et al., 2018) screened literature reports of cases and groups of cases of Gukang Capsule-induced liver injury, as well as literature reports of adverse reaction monitoring data after marketing, and analyzed pertinent cases in the literature. According to the results, liver injury was the main adverse reaction to Gukang Capsule, with the risk being primarily related to psoralen. Long-term Gukang Capsule intake, Gukang Capsule use in elderly patients, and liver disease history may be the pre-risk factors for liver injury. Five clinical studies included in this analysis reported adverse reactions associated with drug therapy. However, the meta-analysis revealed no statistically significant difference in the frequency of adverse reactions between the Gukang Capsule group and the control group. Furthermore, no serious side effects were reported, and the most common adverse events were mild gastrointestinal issues such as nausea and diarrhea. These findings suggest that Gukang Capsule does not appear to increase the risk of side effects and may be a relatively safe option as a complementary or alternative treatment for POP.

The ‘Consensus’ suggests that Gukang capsule for the treatment of OP, if there is a combination of drugs should be cautious, should not be combined with hepatotoxic drugs. The consensus adverse reactions of taking Gukang capsule were summarized. Adverse reactions of digestive system included: nausea, vomiting, poor appetite, gastrointestinal discomfort, abdominal pain, diarrhea, abdominal distension, constipation, abnormal liver biochemical indexes, etc. Skin and accessory adverse reactions include: rash, pruritus, etc. Other adverse reactions include dizziness, headache, fever, fatigue, and dark urine color. It is recommended to take Gukang capsule after meals, stop taking medicine immediately when adverse reactions occur, go to relevant departments for diagnosis and treatment, and recommend liver function examination (Zhu et al., 2022).

This study has the following limitations. (1) None of the studies employed double-blinding or allocation concealment, and overall study designs lacked rigor. This raises concerns about potential bias in the results. (2) The studies used a variety of drug combinations and treatment durations. This inconsistency makes it difficult to establish a standardized treatment regimen for Gukang Capsule. (3) Evaluating the long-term effectiveness and safety of Gukang Capsule requires extended follow-up data, which was missing in many of the included studies. (4) The studies were limited to China, as Gukang Capsule is not standardized in other countries. This geographic limitation may introduce publication bias. (5) Positive results are generally more likely to be published and cited than negative findings. This can lead to biased conclusions in meta-analysis.