Osteoporosis (OP) is a condition characterized by a decrease in bone density and the deterioration of bone tissue, which leads to increased bone fragility and a higher risk of fractures (Jiang et al., 2024). It commonly affects older adults, particularly postmenopausal women, due to decreased estrogen levels which accelerate bone loss. Symptoms of OP may include back pain, a loss of height, and frequent fractures, often occurring in the spine, hip, or wrist with minimal or no trauma (Camacho et al., 2020; Li et al., 2024). In recent years, the incidence of OP has gradually increased with high rates of multiple complications and mortality (ACOG, 2022).

OP is classified into primary and secondary OP according to the etiology. Typically, primary OP (POP), including postmenopausal osteoporosis (PMOP) and senile osteoporosis (SOP), is treated with some medications such as bisphosphonates (BPs), denosumab, selective estrogen receptor modulators (SERMs) and teriparatide (a kind of Parathyroid Hormone Analogs) (Meng et al., 2024). Early detection and appropriate treatment can help manage OP effectively and reduce the risk of fractures and mortality. However, the long-term safety and efficacy of these medications remain a concern, and issues such as potential side effects, including atypical femoral fractures and osteonecrosis of the jaw, continue to be debated (Wei et al., 2024). There is a long history of using traditional Chinese medicine (TCM) for the treatment of various diseases. In recent years, TCM has become an effective alternative for the treatment of OP, and some TCM treatments and active ingredients have become popular with doctors and patients due to their ease of use, therapeutic effect comparable to Western medicine, and minimal side effects (Wei et al., 2024; Zhou et al., 2024).

According to the relevant guidelines, Epimedium total flavonoids (EF) is one of the effective components in TCM of which the drug efficacy is relatively clear (Zhenlin, 2023). Many excellent studies reported some unexpected therapeutic effects of some effective components on some certain diseases (Ullah et al., 2024). Modern pharmacological experiments have shown that the main ingredients of EF include icaritin, Baohuoside and epimedin. Large number of basic research have shown that the EF could improve the osteogenic capability in the animal and cell model. It was demonstrated that the EF could regulate bone metabolism, increase bone mass in osteoporotic rats by up-regulating the expression of TGF-β1 and Smad2 (Xiao et al., 2022). Other studies showed that the EF could inhibit the apoptosis of osteoblasts to promote the bone formation and inhibit osteoclast generation to decrease the bone absorption (Xia et al., 2023). There was a study reported that the EF could ameliorate osteoporosis in ovariectomized rats by targeting Cullin 3/Nrf2/OH pathway for osteoclast inhibition (Si et al., 2024). Another study found that the EF could ameliorate POP by targeting AKT/mTOR/ULK1 autophagy signaling pathway (Zou et al., 2024). By the way, other authors reported in their study that EF could promote the proliferation and osteogenic differentiation of bone-derived mesenchymal stem cells in patients with osteoporosis and T2DM by upregulating GLI-1 (Xia et al., 2023). Moreover, the EF capsule, a kind of Chinese patent medicine of which the EF is the major active ingredient, has already been approved for clinical use by the National Medical Products Administration (NMPA) of the People’s Republic of China and listed on the market (approval number: national drug standard Z20140012).

Although there are many basic research studies on EF on POP treatment, there is still a dearth of relevant evidence-based medical data on EF efficacy and safety. Therefore, we conducted a systematic review and meta-analysis on the efficacy and safety of EF in POP treatment, providing a reference for the appropriate application of EF in clinical practice.

This research was registered with the international prospective register of systematic reviews (PROSPERO number: CRD42024550573). This work has been reported in line with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses).

As the world’s population ages, the incident rate of POP is increasing globally (Chen et al., 2024). POP, because of its tendency to lead to osteoporotic fractures, is a major risk factor for disability and even death of older patients and can significantly impair the quality of life (Shen et al., 2024). POP has been a major worldwide public health problem. At present, interventions for POP include inhibiting bone resorption and promoting bone formation. However, treatment with western medications alone remains controversial. TCM has shown effective in treating POP. Many TCM compounds used to treat POP contain Epimedium as a major herb (Shou et al., 2009). EF, as one of the effective ingredients of Epimedium, has been described to display anti-osteoporosis effects by lots of basic research. Meanwhile, EF capsules are already on the market for POP. The aim of this systematic review and meta-analysis was to evaluate the clinical efficacy and safety of EF in the treatment of POP and serve clinical evidence.

In this study, 6 outcomes were compared including lumbar vertebra BMD, femoral neck BMD, serum P1NP levels, serum CTX levels, serum BALP levels and total complications in the meta-analysis. At the same time, some other outcomes which were insufficient to conduct meta-analysis were also reported as the part of systematic review. As for the BMD, the outcome of meta-analysis showed that the lumber vertebra BMD in EG was significantly higher than CG (P < 0.05) with no heterogeneity. But the pooled 95%CI nearly crossed the invalid line (Figure 3). Therefore, although the statistical difference was meaningful, the clinical difference between two groups was considered small. Moreover, about the femoral neck BMD, the difference was neither statistically nor clinically meaningful (Figure 4). Our results were similar to other studies. In Shou’s study, the authors described the Ward’s triangle BMD, greater trochanter of femur BMD and hip BMD after EF treatment, and the result showed that there was no significant difference between EG and CG (Shou et al., 2009). Another study reported the significant difference between EG and CG about the rate of change in BMD (Lu et al., 2013). The authors observed that the outcome in the EG was significantly better than in the CG, but they did not describe specific values of BMD. Many basic studies have reported that the EF could improve the proliferation and osteogenic differentiation of osteoblasts and inhibit the activity and osteoclast differentiation of osteoclasts (Si et al., 2024; Yang et al., 2024; Zhang et al., 2024). Our data exhibited that there was no superior efficacy compared to the CG, including other Chinese patent medicines, Calcium and vitamin D supplements. The EF gained the comparable efficacy compared with these medicines. Bone reconstruction is a dynamic and complicated process, and the change of the BMD is influenced by many factors. Therefore, we thought that an idealized increase in BMD is difficult to achieve.

About the serum biomarkers, we compared the levels of P1NP, CTX and BALP. P1NP and BALP were typical biomarkers of osteogenic ability, CTX was typical biomarkers of osteoclastic abilities. We observed that the levels of P1NP and BALP in EG was higher than CG and the level CTX in EG was lower than CG. Our observations are similar to the previous study (Zhang et al., 2021; Zou et al., 2024). However, the results of this study also showed that there was no statistically significant difference between two groups among these three comparisons. Besides, the pooled 95%CI crossed the invalid line among these three comparisons (Figures 5–7). Thus, similar to the BMD, the effect of EF was comparable to the treatment in CG among the levels of serum biomarkers. However, the heterogeneity in these comparisons were relatively high. This might be because of that there were only two studies included in these comparisons causing the sensitive analysis was not able to be conducted. We have used the random effects model to conduct meta-analysis to minimize the heterogeneity.

About the safety of the treatment of EF, we evaluated the total complications in the meta-analysis. Our results revealed that the rate of total complications in EG was lower than CG but the difference between two groups was not statistical and the pooled 95%CI crossed the invalid line (Figure 8). No serious specific complications were reported in all studies. This is similar to the findings of Yong et al. and others (Jin, 2019; Yong et al., 2021). It is worth noting that in Yong’s study, the authors tested the levels of some biochemical parameters including hepatic markers, hematological markers and renal markers. The author did find some levels outside the normal range, but all these changes reverted to normal subsequently and no substantial adverse clinical consequences was observed. Given this, the EF has a relatively good safety profile.

Some other outcomes that were insufficient for meta-analysis were also documented. These outcomes included bone formation marker (OC), bone absorption markers (DPD and TRAF6) and general markers (E2, serum calcium and phosphorus). In general, the EF could decrease bone absorption markers and increase the bone formation marker. However, most of these differences were not significant (Zhang et al., 2007; Shou et al., 2009; Yong et al., 2021).

There are some limitations in the present study. Firstly, the number of studies that met the inclusion criteria was relatively small, causing the inability to conduct a more comprehensive meta-analysis. Secondly, the number of high-quality studies was small, and the quality of the evidence was low and moderate based on the GRADE analysis, which may affect the credibility of the results of our meta-analysis. Thirdly, evaluating the long-term effect and safety of the EF requires extended follow-up data. Fourthly, the studies were limited to the country or region a country whose majority population is ethnic Chinese, and publication bias might be introduced, but it was not assessed in the present study because of the small number of included studies. Fifthly, common therapeutic drugs for treatment of POP like BPs were not presented in the included studies. Meanwhile, this article has some advantages. Our results revealed that EF could achieve good clinical effects and safety in terms of improving BMD and reducing complications. As far as we know, the present study was the first study to conduct a meta-analysis about the efficacy and safety of EF on POP, which might fill the relevant knowledge gap and provide the clinical guidance and evidence.

The present systematic review and meta-analysis revealed that the EF treatment for POP could achieve good curative effects and safety. Based on the findings of this study, the conclusion cannot be drawn that the EF exhibit better efficacy and safety compared with other Chinese patent medicines, Calcium and vitamin D supplements. The safety profile of the EF treatment was good which was comparable to other medications addressed above. The EF treatment was proved to be a reliable alternative option for POP. Regrettably, no RCT with high quality was included in our study and the quality of evidence provided by the present study was not assessed as high. In the future, more well-designed clinical trials with a large participant pool and extended follow-up time are needed to increase the quality of evidence and synthesize more data.