This systematic review and meta-analysis of 7 studies involving  475 male patients revealed significant improvements in the percentage of men with lessening of penile plaques, penile curvature, relief of pain and complete remission.

Although satisfactory results were obtained from numerous studies, the mechanism of LI-ESWT’s effect in PD remains unclear. Numerous studies have demonstrated that LI-ESWs can induce cell proliferation, angiogenesis, and facilitate tissue regeneration [18]. LI-ESW stimulates the focal adhesion kinase, extracellular-signal-regulated kinase, PERK, ATP/P2 × 7, and Wnt signaling pathways, leading to cell proliferation, endothelial and smooth muscle restoration [19]. It is hypothesized that LI-ESWT may play a significant role in plaque remodelling and direct damage, leading to consecutive resorption of calcification and softer plaque, ultimately resulting in further correction and/or resolution of penile curvature [20]. Second, Research indicates that LI-ESWT enhances the expression of multiple angiogenesis-related factors, such as VEGF, IL-8, stromal cell-derived factor 1, eNOS, CXC motif chemokine 4, and basic fibroblast growth factor. Additionally, it improves tissue perfusion in both clinical trials and animal models(19, 21–22). LI-ESWT enhances penile hemodynamics in patients with PD, and the local circulation may be increased due to the generation of heat caused by this treatment, which can trigger an inflammatory reaction and subsequently enhance macrophage activity, resulting in plaque lysis and resorption [23]. LI-ESWT has the potential to trigger anti-inflammatory responses through the mechanism of mechanotherapy, while also inducing diverse biological responses and immune regulatory pathways. LI-ESWT has the ability to inhibit the production of proinflammatory cytokines (such as IL-1α, IL-4, IL-6, etc.), chemokines (like CCL2, CCL12, etc.), and matrix metalloproteinases (MMPs) by stopping their production [18]. LI-ESWT is administered at different time points, and energy has different effects on the inflammatory process [24].

Although we stress that our study is not the first systematic review and meta-analysis to cover the use of LI-ESWT in PD, we believe our study has significant strengths and limitations. In a previous meta-analysis of clinical trials, it was found that LI-ESWT was effective in treating penile pain and sexual dysfunction [20]. However, one important flaw in their analysis, as admitted by the authors, is the heterogeneity of study populations and methods across intervention trials and control groups [20]. According to a meta-analysis published by Fojecki GL et al., two out of three studies on PD reported significant improvement in pain, yet no clinically significant changes were observed in penile deviation and plaque size, however, a meta-analysis was not conducted [25]. The meta-analysis conducted by Gao L et al. concluded that LI-ESWT improved pain, curvature, and plaque size, however, it did not show a statistically significant improvement in erectile function. Nevertheless, the meta-analysis encompassed a limited number of low-quality publications, diverse shockwave generators, varied protocols, and diverse inclusion and exclusion criteria. While acute side effects were reported, no studies have explored the long-term effects or consequences.The longest follow-up period was 6.5 months [26].

To summarize, the meta-analysis mentioned above included only three randomized placebo-controlled clinical trials. Only one meta-analysis was conducted, which included comparative (nonrandomized) studies along with three randomized controlled trials. Due to the missed majority of required data, a meta-analysis cannot be completed. Bakr AM et al. therefore analyzed the available data and estimated the missing data whenever feasible [27]. They propose that LI-ESWT does not enhance the curvature of the penis or pain in men with PD. However, their study also has limitations. RCTs utilize various metrics to indicate the same outcome.The data that were missed were imputed to satisfy the meta-analysis requirements. Furthermore, there exists a significant amount of data that remains unestimateable [27].

Our meta-analysis presently comprises the outcomes of the most trials. Shalom J’s [28] study is the first to report on the long-term results of LI-ESWT for Peyronie’s disease, with a mean follow-up of approaching 4 years. Despite the greatest criticism towards this and other LI-ESWT studies being the absence of a control group, their longitudinal data suggest that LI-ESWT has a positive impact on Peyronie’s disease, such as a reduction in angulation.The study by Sokolakis I et al. demonstrated that LI-ESWT is a safe and effective treatment option for pain management in both the short- and long term. No significant differences were observed between the two groups in terms of improving penile curvature or sexual function [29].

This systematic review and meta-analysis aimed to investigate the effectiveness of LI-ESWT in treating PD. Nevertheless, our study encountered certain limitations. There is controversy over whether LI-ESWT can reduce plaque size in PD. Some studies hold a negative view [11,12,13, 16]. Different studies use different measurement methods, including subjective and objective methods, to obtain different conclusions. Shimpi et al.uses both scoring method and ultrasound detection to show that LI-ESWT can reduce plaques [30]. This meta-analysis also shows that shock wave therapy can increase the percentage of men with lessing of penile plaques used as a qualitative evaluation index, which is consistent with the meta-analysis of Gao L et al. [26] and Bakr AM [27]. However, if plaque size is evaluated using objective measurable indicators, there is no significant improvement in plaque size reduction in the LI-ESWT group compared to the control group, indicating that plaque size is notoriously difficult to assess and its impact on peyronie’s outcomes is difficult to interpret. The same situation also exists in the utilization of the degree of curvature as a different subjective and objective therapeutic evaluation indicator. Therefore, it also indicates the need for unified and accurate efficacy evaluation indicators in the future.

Most trials had small sample sizes.In our meta-analysis, the largest sample size only consisted of 102 male patients [16]. Regarding patient demographics, several studies have described the selection criteria and previous treatment strategies. Another important limitation of the included studies is their short-term follow-up. Follow-up was typically limited to approximately 6 months for most studies. Therefore, the robustness of this approach remains unknown, and more long-term data are required. In this meta-analysis, the 7 studies comprised 4 randomized controlled trials and 3 non-randomized controlled trials.In the event of any bias, the outcome of this meta-analysis would be significantly impacted.

Furthermore, our study exhibited a remarkably high level of heterogeneity (I2 = 55-79%). One possible explanation for this heterogeneity could be the selection of subjects and the subsequent therapeutic regimen. In most studies, the energy flux density (EFD) ranged from 0.25 to 0.29 mJ/mm2, while only one study had EFDs as low as 0.07 mJ/mm2 -0.17 mJ/mm2 [13]. The treatment course lasted for either 4 or 6 weeks. Furthermore, Mirone V et al. [10] and Hauck et al. [12] employed the drug therapy group as the control group to uncover the impact of LI-ESWT. Additionally, it should be noted that PD has a natural onset process, and pain typically subsides as it transitions from the active phase to the stable phase. This to some extent affects the conclusions of research with pain as the endpoint, especially the lack of control group studies.

Extracorporeal shock wave therapy (ESWT) has also been employed for urological indications since the mid-1990s. The conventional shock wave lithotriptors utilize higher energy densities (0.5–0.9 mJ/mm2) for treatment. The energy range examined in this review is 0.07–0.5 mJ/mm2, which is not highly accurate and should be categorized as medium to low energy. However, the principal objective of this study is to differentiate it from high energy [31].

In the future, research on LI-ESWT should be based on both basic and clinical science. To comprehend the mechanism of LI-ESWT, extensive fundamental research is required.Several types of equipment are available on the market, each equipped with focused shock sources, including electrohydraulic, electromagnetic, and piezoelectric generators. Different types of equipment require distinct treatment plans. More research is required to assess various devices. There is an urgent demand for well-designed, long-term, multicenter randomized controlled trials to assess the true potential and ultimate usage of such devices in Peyronie`s disease patients.