Deciphering the function and mechanism of extracorporeal shock wave therapy in knee osteoarthritis (Review)

Introduction

Osteoarthritis (OA) is the most prevalent musculoskeletal disorder worldwide and one of the leading causes of persistent pain and physical disability (1). Its high prevalence imposes heavy burdens on healthcare systems and substantially impairs patients' daily function and quality of life (2). The pathogenesis of OA is complex and varied, involving a number of factors, including age, sex, climate change and lifestyle, all of which play a role in contributing to the onset and progression of the disease (3). In addition, OA predominantly affects weight-bearing and highly mobile joints (4). As a result, the knee is most susceptible to OA (5), as it is the body's most structurally complex and weight-bearing joint. According to global statistics, ~15% of the population is affected by knee osteoarthritis (KOA), which represents a major global cause of movement impairment and disability (6). KOA is marked by the breakdown of joint cartilage, inflammation of the synovial tissue and abnormal alterations in the underlying subchondral bone. To date, there are no effective clinical methods capable of altering the course of this disease (7,8), underscoring the urgent need for safer and more effective treatment options. Clinical management generally follows a stepwise protocol, prioritizing conservative approaches before considering invasive procedures (9). For early-stage KOA, non-pharmacological interventions remain the gold standard, valued for their demonstrated efficacy, cost-effectiveness and excellent safety record (10,11). When these measures prove insufficient, extracorporeal shock wave therapy (ESWT) has emerged as a widely investigated non-invasive adjuvant intervention, attracting considerable attention for its therapeutic potential in orthopedic conditions, including KOA (12,13). The different common treatments for KOA are shown in Fig. 1.

Figure 1 Different common treatments for KOA. KOA, knee osteoarthritis; TKA, total knee arthroplasty; PRP, platelet rich plasma; NSAIDs, non-steroidal anti-inflammatory drugs; ESWT, extracorporeal shock wave therapy.

ESWT was first introduced in the 1970s for urinary tract lithotripsy (14) and later gained recognition in musculoskeletal medicine following the incidental observation of osteoblastic activity in animal models (15). Today, ESWT is widely investigated for various orthopedic conditions, including KOA (16,17). Notably, while ESWT as an adjunctive treatment for OA was still in the exploratory stage and lacked standardized protocols, veterinary medicine pioneered its application in equine KOA, providing an initial basis for clinical exploration (18). A series of preclinical animal experiments have demonstrated that ESWT intervention can delay pathological progression of KOA, relieve joint pain and improve locomotor function, alongside observable chondroprotective effects in animal OA models (12,19-21). Furthermore, when ESWT was applied to human participants, multiple clinical trials validated its analgesic and functional recovery effects (22-24). Targeting the affected area and transmitting high-energy acoustic pulses into the body of the patient is considered the therapeutic principle of ESWT. As an acoustic high-voltage wave produced through electric, electromagnetic, piezoelectric or ballistic/radial means, ESWT is believed to possess the ability to degrade fibrous tissue, break down calcifications, stimulate blood circulation, promote cell proliferation and repair tissue through its mechanical impact force (25). This biological cascade can improve the metabolism and function of chondrocytes, support cartilage integrity and promote tissue repair (25-27).

Despite encouraging progress, the precise mechanisms by which ESWT exerts its therapeutic effects in KOA remain incompletely understood, and clinical protocols are yet to be standardized. The present review summarizes current preclinical and clinical evidence on ESWT for KOA, with a focus on its biological mechanisms, therapeutic efficacy and parameter optimization. By clarifying the current state of knowledge and identifying key knowledge gaps, the review aims to provide a theoretical framework for future mechanistic investigations and evidence-based clinical decision-making.

Search strategy

The present narrative review retrieved literature from PubMed (https://pubmed.ncbi.nlm.nih.gov/), EMBASE (https://www.embase.com), Web of Science (https://www.webofscience.com) and the Cochrane Library (https://www.cochranelibrary.com) from database inception to July 2026. Search terms combined MeSH headings and synonyms using Boolean operators. The specific terms and indexing syntax were adapted to each database's vocabulary (for example, MeSH for PubMed and Cochrane Library, Emtree for EMBASE and topic search for Web of Science). The following are representative examples: Block 1 (knee osteoarthritis): 'osteoarthritis, knee' [MeSH], knee osteoarthritis, gonarthrosis; Block 2 (ESWT): 'extracorporeal shockwave therapy' [MeSH], extracorporeal shock wave, shock wave, ESWT. Terms within each block were linked by OR, and two blocks were combined by AND.

The following inclusion criteria were applied: Studies related to the mechanisms and therapeutic approaches of ESWT in KOA. The following exclusion criteria were applied: Irrelevant studies as screened by title/abstract; studies missing method and/or results details; non-English articles and studies in which ESWT was not used as the primary intervention.

The screening and selection process is summarized in the PRISMA-compliant flow diagram (Fig. 2), which was designed according to the PRISMA 2020 statement (28). A total of 583 records were initially identified. After removing duplicates, 361 records were screened by title and abstract. Of these, 214 full-text articles were assessed for eligibility. Finally, 85 studies met the inclusion criteria and were included in this review.

Figure 2 Article retrieval flow chart with inclusion and exclusion process. ESWT, extracorporeal shock wave therapy.

Basic overview of ESWT in KOA

As a form of mechanotherapy, ESWT delivers mechanical pulsed pressure waves to target tissues. Clinically, ESWT can generally be categorized as focused and radial types, both of which have been proven to provide positive outcomes for patients with KOA. In physical terms, both focused and radial waves are forms of mechanical waves, yet they exhibit distinct waveform shapes (29). However, focused waves are more effective than radial waves in influencing deeper tissues (30). Unlike focused waves, radial waves tend to disperse energy over a broader area, affecting shallower tissues, whereas focused waves concentrate on specific deep tissue targets (31). Focused ESWT (f-ESWT) is generated by electromagnetic, electrohydraulic or piezoelectric mechanisms, producing a focused beam shape that converges energy at a defined depth. By contrast, radial ESWT (r-ESWT) is generated pneumatically and produces a diverging beam, with energy peaking at the skin surface and attenuating rapidly with tissue depth (32). As a result, f-ESWT delivers higher energy density to deeper targets, such as the bone-cartilage interface, whereas r-ESWT primarily affects more superficial tissues (30).

These physical distinctions have implications for the clinical application of ESWT across different stages of KOA. From a mechanistic standpoint, f-ESWT appears better suited for treating deep structural pathologies, such as subchondral bone remodeling or bone marrow lesions, where its superior penetration and focal energy delivery may offer a theoretical advantage (33). Conversely, r-ESWT may be preferred for superficial tissue involvement or early-stage KOA, where broad energy dispersion over a larger area may be sufficient for symptom relief (34,35). However, the distinction is not absolute; preliminary evidence also suggests that r-ESWT combined with conventional therapy may provide functional benefits even in advanced KOA (grade IV), though confirmatory studies are still needed (36). Direct comparative evidence between the two waveform types remains limited, and the optimal choice for individual patients should be guided by the predominant pathological features (for example, deep osseous lesions vs. superficial soft-tissue inflammation) and disease severity.

Despite the physical discrepancies between the two shock wave modalities, the mechanical pulsed stimulation delivered by either type serves as the fundamental trigger for subsequent tissue and cellular biological reactions.

By delivering mechanical stimulation across molecular, cellular and tissue-level structures, it not only alleviates or repairs damage in affected tissues but also promotes the development of healthy tissue (37). The biological response induced by this mechanical stimulation is deemed to be the main pathway by which ESWT exerts treatment efficacy in its clinical applications (38). In the short term, this leads to heightened intracellular tension, enhanced cell adhesion, and increased cell movement (39). The long term outcomes appear to involve various interconnected signaling routes (40). However, the underlying mechanisms of how cells and tissues react to mechanical force signals, as well as how they translate them into intercellular bio-signals that remodel their microenvironments and govern their own behaviors, remain to be thoroughly investigated. Some researchers propose that the theory of cellular mechanotransduction may explain this (41).

The ability of cells to perceive mechanical stimuli within their specific microenvironment is defined as mechanosensation, whereas the process by which cells convert these mechanical signals into corresponding biological responses and adjust their physiological functions is termed mechanotransduction (42). During the administration of ESWT, shock waves exert pressure on the extracellular matrix (ECM), triggering morphological changes and altering interstitial fluid movement. This mechanical pressure also activates sensory units on the cell membrane, leading to cytoskeletal rearrangements that enable direct coupling with force-sensitive ion channels, thereby forming a mechanical signaling pathway (43).

Integrins, which connect the ECM to the cytoskeleton as integral transmembrane proteins, play a pivotal role as mechanical sensors in ESWT-induced signaling processes (44). Cells sense and respond to the physical properties of their surrounding environment through specialized adhesion sites mediated by integrins. At these focal adhesions, integrins function as bridges linking the ECM to the intracellular F-actin cytoskeletal network. Furthermore, they facilitate the transmission of mechanical forces into the ECM through mechanosensitive adherens proteins that function collectively as force-transmitting molecular linkages. This force transmission establishes a dynamic mechanical interplay between the viscoelastic properties of the ECM and intracellular cytoskeletal tension. As mechanotransduction proceeds, these mechanical forces induce conformational changes in mechanosensitive proteins within adhesion complexes, ultimately triggering downstream biochemical signaling cascades that regulate cellular behavior (45).

In addition, ion channels are recognized as important contributors to mechanotransduction. The regulated influx and efflux of ions across the cell membrane support cellular adaptation to mechanical stress by facilitating downstream biochemical responses (46). When cells interpret external mechanical signals, a cascade of biological events is initiated, including modulation of gene expression, regulation of protein synthesis and alterations in cellular metabolism (29). Studies have further demonstrated that ESWT enhances the activity of key growth factors, such as insulin-like growth factor 1, vascular endothelial growth factor (VEGF), bone morphogenetic protein (BMP) and transforming growth factor-β1, all of which are essential for cartilage development, tissue regeneration and cellular proliferation (15,29,30,47). Collectively, these effects substantially broaden the therapeutic potential of ESWT. Fig. 3 illustrates the mediators involved in cellular mechanotransduction, highlighting the contributions of multiple molecules, cellular components and extracellular structures. The mechanotransduction process operates through distinct molecular signaling pathways. As illustrated in Fig. 4, ESWT applies mechanical stimuli to the knee joint affected by KOA. Mechanical cues are sensed by multiple cell-surface sensors that transduce physical force into intracellular mechanotransduction signals within joint-resident chondrocytes. Membrane receptors, such as TLR-4, integrin, Frizzled, pannexin-1 channel and growth-factor receptors initiate downstream signaling cascades primarily involving PI3K-AKT, NF-κB and MEK-ERK pathways, among others. This network ultimately drives four principal chondroprotective phenotypes: Suppression of inflammation, inhibition of chondrocyte apoptosis, enhancement of cell proliferation, and preservation of cartilage homeostasis, via regulating effector molecules such as NO, CDK1, PCNA and MMPs (19,39,41,48). Several minor auxiliary signaling branches are excluded from this schematic to highlight core therapeutic mechanisms.

Figure 3 Mediators of cellular mechanical transduction. The mediators involved in cellular mechanical signaling are illustrated, highlighting the roles played by various molecules, cellular components and extracellular structures. The mechanotransduction process operates through distinct molecular signaling pathways. ECM, extracellular matrix.

Figure 4 Important signal transduction process of ESWT in KOA. The signal transduction process of ESWT in KOA is illustrated, highlighting the key mechanisms involved in the treatment while omitting less relevant pathways. ESWT, extracorporeal shock wave therapy; KOA, knee osteoarthritis; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-α; ATP, adenosine triphosphate; IGF, insulin-like growth factor; VEGF, vascular endothelial growth factor; BMP, bone morphogenetic protein; TGF-β, transforming growth factor-β; MyD88, myeloid differentiation factor 88; TRAF6, TNF receptor-associated factor 6; NLRP3, NOD-like receptor family pyrin domain-containing 3; NF-κB, nuclear factor-κB; NO, nitric oxide; YAP, yes-associated protein; CCNA2, cyclin A2; PI3K, phosphatidylinositol 3-kinase; AKT, serine/threonine kinase (or protein kinase B); FAK, focal adhesion kinase; CDK1, cyclin-dependent kinases 1; DKK-1, dickkopf-1; MEK, mitogen-activated protein/extracellular signal-regulated kinase kinase; ERK, extracellular regulated protein kinases; PCNA, proliferating cell nuclear antigen; STAT, signal transduction and activation of the transcription factor; MMPs, matrix metalloproteinases.

Molecular and cellular mechanisms of ESWT in KOA

Cumulative studies have suggested that ESWT may exert a protective effect on KOA through multiple mechanisms, including anti-inflammatory properties, anti-apoptotic effects, promotion of cell proliferation and maintenance of cartilage homeostasis (49-51). Consequently, ESWT has attracted considerable research interest as a potentially valuable complementary and alternative approach for KOA. This review summarizes the most recent studies exploring the molecular mechanisms triggered by ESWT and the signaling pathways involved in managing KOA. This section will outline the underlying mechanisms through which ESWT may exert its effects on joint tissues. Fig. 5 illustrates the mechanism of ESWT in KOA, focusing on the key activities involved in this process and omitting other less relevant mechanism details.

Figure 5 Mechanism of ESWT in KOA. The mechanism of action of ESWT in KOA is illustrated, focusing on the key activities involved in this process and omitting other less relevant mechanism details. ESWT, extracorporeal shock wave therapy; KOA, knee osteoarthritis; STAT, signal transduction and activation of the transcription factor; PI3K/AKT, phosphatidylinositol 3-kinase/serine/threonine kinase/protein kinase B; YAP, yes-associated protein; ERK, extracellular regulated protein kinases; DKK-1, dickkopf-1; NF-κB, nuclear factor-κB; MMP, matrix-metalloproteinase; NLRP3, NOD-like receptor family pyrin domain-containing 3.

Anti-inflammatory mechanism of ESWT

In studies examining the pathophysiological progression of KOA, increasing attention has been directed toward anti-inflammatory strategies, with inflammation regulation emerging as a central therapeutic focus (49). Although nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for conservative KOA management (31), their gastrointestinal and cardiovascular adverse events limit long-term application, especially in patients with comorbidities. As a safer alternative physical intervention, ESWT has garnered substantial research attention for its anti-inflammatory efficacy in KOA treatment (52-54). ESWT has been shown to increase the expression of the anti-inflammatory factor IL-10 in chondrocytes and osteoblasts (55,56); furthermore, it reduces the expression of the pro-inflammatory factor tumor necrosis factor α (TNF-α) in chondrocytes, thereby potentially interfering with the pathological mechanisms underlying cartilage damage in OA (56). Existing evidence indicates that ESWT may exert anti-inflammatory effects through activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway (57). PI3K has been shown to suppress activation of nuclear factor-κB (NF-κB), a key transcription factor responsible for regulating the expression of multiple pro-inflammatory genes (58). Accordingly, inhibition of NF-κB activity is widely regarded as an effective strategy for attenuating inflammatory responses. ESWT is believed to regulate the inflammatory cascade by suppressing NF-κB signaling and its downstream targets, including inducible nitric oxide synthase (iNOS), TNF-α, intercellular adhesion molecule, vascular cell adhesion molecule-1 and cyclooxygenase-2 (COX-2) (54).

NO appears to play a complex role in this regulatory process. Physiological levels of NO contribute positively to immune defense and tissue homeostasis (59), and moderate NO concentrations can exert cytotoxic effects that facilitate the elimination of damaged or invading cells (31). By contrast, excessive NO production can react with superoxide to generate peroxynitrite, a highly reactive molecule that induces severe inflammatory tissue damage (60). Notably, NO can function as a potent inhibitor of NF-κB activation when maintained within low physiological concentrations, typically below 50 nM (61). Although increased NO is observed in osteoarthritic cartilage, evidence suggests that ESWT can modulate NO levels, potentially restoring them to a beneficial physiological range, leading to suppression of NF-κB activity and resolution of inflammation.

In addition, the yes-associated protein (YAP) signaling pathway has been identified as an important negative regulator of NF-κB activity in OA (62). YAP protein has been shown to bind to the transforming growth factor-β-activated kinase 1-IκB kinase (IKK) complex, thereby inhibiting IKKα/β activation and preventing NF-κB nuclear translocation (62). Given that ESWT can activate YAP, as demonstrated in experimental settings (63), this mechanism may further contribute to NF-κB inhibition.

Beyond its regulatory roles as aforementioned, NF-κB signaling is also a key determinant of macrophage phenotype (64). Macrophages are intrinsically mechanosensitive (65) and convert physical stimuli into biochemical signals through mechanosensors such as integrins and ion channels (66). Mechanical stimuli activate cytoskeletal remodeling and downstream transcriptional programs that dictate macrophage polarization (67). Direct evidence for ESWT in this context is emerging. ESWT has been shown to potentially drive the M1-to-M2 phenotypic transition through mechanical transduction that converges on the NF-κB pathway (68-70). Collectively, these findings indicate that ESWT promotes an M1-to-M2 phenotypic shift, likely through mechanotransduction pathways that converge on NF-κB and potentially other signaling networks. Nevertheless, the tissue-specific molecular regulatory details unique to the complex synovial microenvironment remain to be fully elucidated.

Furthermore, ESWT attenuates inflammatory responses by suppressing toll-like receptor 4 (TLR4) signaling (71). As a pattern recognition receptor, TLR4 plays a critical role in pathogen detection and serves as a key mediator of both innate and adaptive immune responses (72,73). Importantly, focusing on TLR4 as a therapeutic target shows great potential for mitigating inflammation without compromising the body's natural immune defenses (74). TLR4-mediated signaling relies heavily on myeloid differentiation factor 88 (MyD88), which initiates downstream inflammatory signaling upon receptor activation (75,76). MyD88 interacts with TNF receptor-associated factor 6 (TRAF6), leading to NF-κB activation and nuclear translocation, thereby triggering transcription of inflammatory genes (77). Blocking the TLR4/MyD88/NF-κB signaling axis has been shown to markedly reduce inflammatory responses (78).

NF-κB signaling also positively regulates activation of the NOD-like receptor family pyrin domain-containing (NLRP3) inflammasome. Dose-dependent inhibition of NLRP3 activation has been observed following pharmacological blockade of NF-κB, underscoring its essential role in inflammasome initiation (79). Overexpression of NLRP3 promotes the maturation of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and IL-18, thereby amplifying inflammation (80). Consistent with these findings, inhibition of NLRP3 activity has been shown to reduce the inflammatory response (81). Together, these studies highlight the role of ESWT in modulating NF-κB-related inflammatory pathways.

Anti-apoptotic mechanism of ESWT

Excessive chondrocyte apoptosis is a pathogenic mechanism of KOA (4), and the number of apoptotic cells correlates with disease severity (82). Therefore, targeting chondrocyte apoptosis offers an effective strategy to limit KOA progression (83). ESWT reduces chondrocyte apoptosis and exerts protective effects on cartilage and subchondral bone (84,85).

Notably, ESWT inhibits expression of dickkopf-1 (DKK-1) protein, a pro-apoptotic factor upregulated in KOA chondrocytes (86). This inhibition reduces apoptosis through at least two downstream pathways: i) Restoring AKT phosphorylation, which inactivates the pro-apoptotic factor B-cell lymphoma-2-associated agonist of cell death (87,88); and ii) enhancing the anti-apoptotic function of Bcl-2, which prevents mitochondrial permeability transition and cytochrome c release (89), a mechanism implicated in the pro-survival effects of DKK-1 inhibition (90). In vitro experimental results further support the aforementioned mechanism regulating mitochondrial apoptosis. Consistent with the aforementioned signaling cascade, ESWT markedly downregulates the protein levels of cytochrome c and caspase-3 in chondrocytes (84). Meanwhile, ESWT efficiently elevates chondrocyte BCL-2 protein expression, strengthening the endogenous anti-apoptotic defense system (85). Collectively, these cellular findings provide functional evidence supporting the anti-apoptotic activity of ESWT and its regulatory effect on mitochondrial apoptotic signaling. Notably, although existing studies have clarified the sequential DKK-1 downstream cascades and verified the corresponding molecular expression changes at the cellular level, two key questions remain unaddressed: i) Whether ESWT directly targets individual downstream signaling molecules and ii) what the hierarchical regulatory relationships among these pathways are. Overall, these findings suggest that ESWT may exert its chondroprotective effects by regulating multiple interconnected upstream and downstream anti-apoptotic signaling pathways through the DKK-1 axis.

Furthermore, ESWT-mediated suppression of NF-κB may contribute to chondroprotection by attenuating pro-apoptotic signaling. Research indicates that NF-κB actively mediates chondrocyte apoptosis in arthritic conditions (91). NF-κB is a central mediator of IL-1β- and TNF-α-driven chondrocyte apoptosis, promoting the expression of catabolic factors [matrix metalloproteinases (MMPs) and COX-2] and pro-apoptotic regulators [Poly(ADP-ribose) polymerase and caspase-3] (92-95). NF-κB also downregulates integrin β1 (93), thereby diminishing cell-matrix interactions and suppressing the protective extracellular regulated protein kinases (ERK)/BCL-2 survival pathway (96-99). While these NF-κB-dependent apoptotic cascades are well characterized in OA, direct evidence linking ESWT to each of these downstream nodes remains incomplete, and further mechanistic studies are needed to clarify which branches are primarily targeted by ESWT.

Pro-proliferative mechanism of ESWT

The decline in chondrocyte proliferation is strongly linked to cartilage degradation, a hallmark sign of advancing arthritis (3,100). ESWT has been shown to enhance the proliferative capacity of chondrocytes, osteoblasts and subchondral bone marrow stem cells to counteract degenerative changes in KOA. These findings suggest that ESWT's ability to stimulate cellular proliferation plays a crucial role in slowing the progression of KOA (29,41). At the molecular level, ESWT upregulates cyclin A2 and its partner cyclin-dependent kinase 1, thereby accelerating the G1/S-to-G2/M transition and increasing cell cycle progression (31,101,102). This effect is rapid, with mitotic activity detectable within 24 h and proliferation significantly increased by 72 h (102).

In addition, ESWT can also stimulate cell proliferation through adenosine triphosphate (ATP) release. Mechanical stimulation opens Pannexin-1 channels, leading to ATP release (103). Once released, ATP activates p38 MAPK and mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2-ERK1/2 signaling cascades, which converge to promote cell proliferation (39).

Moreover, ESWT has been reported to promote cell proliferation by increasing the production of proliferating cell nuclear antigen (PCNA) (31). As a non-histone nuclear polypeptide that is crucial for cell proliferation, the intracellular accumulation of PCNA can serve as an indicator of proliferative activity (104). Following ESWT treatment, PCNA expression is markedly upregulated, triggering the signal transducer and activator of transcription 3 (STAT3) signaling pathway (105). STAT3 acts as a crucial intracellular signaling mediator that stimulates the transcriptional activation of numerous genes associated with growth promotion. Ultimately, this cascade of STAT3 activation results in enhanced cell proliferation (106).

Additionally, ESWT enhances cell proliferation through the PI3K/AKT/mTOR pathway, which drives cell cycle progression and division (107-110). The PI3K catalytic subunit p110α may also contribute to cell migration and proliferation independently of AKT (111), suggesting alternative downstream routes.

Cartilage-homeostasis-regulating mechanism of ESWT

It is well established that cartilage homeostasis, the delicate equilibrium between the synthesis and degradation of the ECM in chondrocytes, plays a pivotal role in maintaining joint health (108). Under conditions of accelerated catabolism and diminished anabolism in articular cartilage, the structural integrity of the cartilage matrix will be compromised (83). Research indicates that when the degradation rate of the ECM notably exceeds its synthetic repair capacity, it inevitably drives the onset and progression of pathological processes associated with cartilage degeneration (112). ESWT is considered to stimulate ECM anabolism while reducing catabolism, which aids in maintaining cartilage homeostasis and thus exerts a chondroprotective effect in the progression of KOA (113).

Under normal physiological conditions, there is a delicate equilibrium between the activity of MMPs and the production of new matrix components. In this setting, the expression of MMPs and their natural inhibitors, tissue inhibitors of metalloproteinases (TIMPs), is carefully controlled to maintain harmony with the synthesis of fresh ECM proteins (93). Yet, in the case of arthritis, this equilibrium between synthesis and breakdown is disrupted; unchecked MMP expression and activity cause excessive breakdown of the ECM, ultimately resulting in the destruction of cartilage (114,115). Within the MMP family, MMP-1, MMP-3, MMP-9 and MMP-13 are recognized as the principal mediators driving cartilage matrix degradation and serve as key contributors to both the development and progression of KOA (116). Among these, MMP-13 is primarily expressed by chondrocytes. Compared to other MMPs, MMP-13 exhibits higher catalytic rates on type II collagen and gelatin, enabling it to be the most efficient peptidase among collagenases (117,118). Beyond that, it also facilitates the breakdown of additional cartilage proteins, including type IV collagen, type IX collagen, perlecan, osteonectin and aggrecan, contributing to accelerated cartilage breakdown (119). In addition, it appears that NF-κB is also involved in regulating the MMP-driven matrix degradation.

ESWT is considered to maintain ECM integrity by inhibiting the pathological overexpression of MMPs (120). The regulation of TIMPs is equally critical in this context, as the MMP/TIMP balance ultimately determines the net rate of ECM degradation (121). Since the direct molecular link between ESWT and TIMP-1 upregulation has yet to be fully established, further mechanistic studies are needed.

NF-κB plays a pivotal role in MMP-driven degradation. NF-κB induces catabolic genes via response elements in MMP-1 and MMP-9 promoters (122,123), and suppresses type II collagen and integrin β1 expression (93). NF-κB also activates transcription factors such as ETS domain-containing protein 1 (ELK-1), hypoxia-inducible factor 2α (HIF-2α), and E74-like factor-3 (ELF-3), which further upregulate MMP-13 and other catabolic mediators (124-126). Functioning as a direct target of NF-κB, the transcription factor ELK-1 can directly enhance basic fibroblast growth factor-induced MMP-13 expression in human articular chondrocytes (127). Studies indicate that under HIF-2α activation, this protein interacts with HIF-2β-specific binding sequences within the promoter regions of catabolic genes, thereby promoting the gene expression process of matrix degrading enzymes (124,125,128). Acting downstream of HIF-2α, CCAAT/enhancer-binding protein-β further fuels OA progression by directly upregulating MMP-13 (129). Meanwhile, ELF-3, another NF-κB-dependent factor, modulates the expression of genes such as iNOS, COX-2 and MMP-13, intensifying cartilage degradation (130).

The activation of PI3K/AKT is believed to promote the synthesis and metabolism of the ECM. AKT phosphorylation has been demonstrated to enhance the production of type II collagen and aggrecan within chondrocytes. Additionally, enhanced AKT signaling, whether through direct overexpression or upstream activation, has been shown to increase proteoglycan synthesis (131,132). Overall, the PI3K/AKT pathway serves as a central regulator in the maintenance of cartilage ECM, influencing both ECM synthesis and degradation. Dysregulation of the pathway can contribute to cartilage degradation and the progression of diseases such as osteoarthritis, highlighting the importance of this signaling pathway in the context of cartilage biology and potential therapeutic targets. These findings also suggest the potential of ESWT in treating KOA by activating the PI3K/AKT pathway.

Beyond its use as a standalone treatment, in combination therapy, ESWT increases the COL2A/COL1A ratio in primary human chondrocytes following hyaluronic acid (HA) administration by inducing CD44 overexpression (133).

Preclinical evidence: In vivo experimental studies

While the preceding section focused on basic molecular and cellular mechanistic evidence, this section presents the preclinical evidence derived from in vivo animal studies that assess proliferation, matrix metabolism and other functional readouts, providing functional validation for the aforementioned mechanisms. Table I summarizes the biological responses to ESWT in predominantly rat models, with one study conducted in rabbits.

Table I Biological responses of ESWT in different animal experiments.

Table I

Biological responses of ESWT in different animal experiments.

Authors, year	Research object type	Models establish	Dosage	Time post operation	Outcome	Conclusion	(Refs.)
Zhao et al, 2012	New Zealand white rabbits	ACLT KOA model	Apply three times within 1 week. 600 impulses of shock waves at 1.5×105 Pa to the left knee once.	4 and 8 weeks	NO↓, caspase 3↓	ESWT may reduce chondrocyte apoptosis and ultimately slow down the progression of KOA by lowering NO levels.	(19)
Wang et al, 2011	Sprague-Dawley rats	ACLT KOA model	EFD of 0.18 mJ/mm2 for 800 impulses.	12 and 24 weeks	vWF↑, VEGF↑, BMP-2↑	ESWT promoted the regression of KOA in rats.	(20)
Wang et al, 2012	Sprague-Dawley rats	ACLT KOA model	EFD of 0.22 mJ/mm2 for 800 impulses.	0, 2, 4, 8 and 12 weeks	VEGF↑, BMP-2↑, type II collagen↑	ESWT can effectively prevent KOA in rats, but its beneficial effects seem to be time-dependent, starting from 4 weeks after treatment.	(21)
Wang et al, 2017	Sprague-Dawley rats	ACLT-MM KOA model	EFD of 0.22 mJ/mm2 for 800 impulses.	12 weeks	PCNA↑, cartilage area↑, un-calcified cartilage↑, calcified cartilage↓	ESWT promotes cartilage proliferation and improves knee joint cartilage injury.	(27)
Wang et al, 2011	Sprague-Dawley rats	ACLT KOA model	EFD of 0.18 mJ/mm2 for 800 impulses.	0, 4, 8 and 12 weeks	Cell proliferation activity↑, chondrocyte apoptosis↓, cartilage degradation↓	ESWT exerts cartilage protection by promoting cell proliferation, increasing chondrocyte activity, and reducing cartilage degradation and apoptosis.	(134)
Chou et al, 2019	Sprague-Dawley rats	Subchon dral bone of medial tibia.	EFD of 0.25 mJ/mm2 for 800 impulses.	12 weeks	TGF-β1↑, DMP-1↓, MMP-13↓, ADAMTS-5↓	ESWT improves tissue regeneration during the progression of KOA lesions.	(137)
Wang et al, 2013	Sprague-Dawley rats	ACLT-MM KOA model	EFD of 0.219 mJ/mm2 for 800 impulses.	12 and 24 weeks	MMP-13↓, type II collagen↑, VEGF↑, BMP-2↑, osteocalcin↑	ESWT can effectively prevent and regress ACLT-induced KOA in rats.	(138)
Wang et al, 2014	Sprague-Dawley rats	ACLT-MM KOA model	EFD of 0.22 mJ/mm2 for 800 impulses.	12 weeks	DKK-1↓, VEGF↑, BMP-2↑, PCNA↑	Early intervention with ESWT can produce cartilage protection during the initial stage of KOA in rats.	(139)
Yılmaz et al, 2017	Sprague-Dawley rats	Induction of KOA by injection of MIA	EFD of 0.18 mJ/mm2 for 800 impulses.	24 h	Osteoblastic activity↑, cell proliferation activity↑	ESWT can promote the proliferation and regeneration of rat cartilage tissue.	(140)
Kim et al, 2019	Sprague-Dawley rats	MIA treated chondrocytes	EFD of 0.068 mJ/mm2 with 500 impulses.	Every 3 days for 2 weeks for a total of four administrations	TNF-α↓, IL-1b↓, IL-6↓, caspase 3↓, Cyt c↓, MMP-3↓, cell viability↑	ESWT exerts a protective effect on cartilage and subchondral bone structures with arthritis by reducing inflammation, cartilage degradation, and chondrocyte apoptosis.	(84)
Cheng et al, 2022	Sprague-Dawley rats	ACLT-MM KOA model	EFD of 0.25 mJ/mm2 with 500 impulses.	Apply ESWT 1 week after surgery.	BV/TV↑, cartilage thickness recovery	ESWT enhances subchondral bone repair while increasing the percentage of trabecular bone volume (BV/TV) and trabecular bone number.	(136)
Chen et al, 2025	Sprague-Dawley rats	Induction of KOA by injection of MIA	ESWT was administered at various levels (0.096, 0.128 or 0.16 mJ/mm2) to determine the optimal dose. The frequency was set at 4 Hz, delivering a total of 800 impulses.	Receive treatment weekly for 4 weeks	Type II collagen↑, MMP-13↓, MMP-3↓, ROS levels↓, G1 phase cell count↓, G2 phase cell count↑	ESWT can alleviate the increase in senescence biomarkers in osteoblasts, mitigate redox dysregulation, stabilize the cell cycle and preserve cartilage integrity. The optimal dose in experiments is 0.096 mJ/mm2	(48)

[i] ↑, significant increase; ↓, significant decrease; ESWT, extracorporeal shock wave therapy; EFD, energy flux density; KOA, knee osteoarthritis; ACLT, anterior cruciate ligament transfer; MM, medial meniscectomy; NO, nitric oxide; caspase-3, cysteine-dependent aspartate-specific protease-3; BMP, bone morphogenetic protein; TGF-β1, transforming growth factor-β1; IL, interleukin; DMP-1, dentin matrix protein-1; MMP, matrix metalloproteinase; ADAMTS-5, aggrecanases-5; vWF, von willebrand factor; VEGF, vascular endothelial growth factor; DKK-1, dickkopf-1; PCNA, proliferating cell nuclear antigen; TNF-α, tumor necrosis factor α; CDK2, cyclin-dependent kinases2; MIA, mono-iodo-asetate; Cyt c, cytochrome c; BV/TV, bone volume/total volume.

Prior studies have found that ESWT exhibits chondroprotective efficacy in the early stages of KOA in rat models (48,134). Notably, further studies have also revealed that this protective effect may be present throughout all stages of KOA development (135). Some preclinical studies suggest possible disease modifying effects (20,27,134,136,137).

Mechanistically, given that ESWT suppresses DKK-1 protein expression, findings from rat KOA models treated with DKK-1-antisense oligonucleotide-mediated DKK-1 inhibition demonstrate that reduced DKK-1 signaling drives nuclear β-catenin accumulation within knee-joint tissues (90), an event that may contribute to the upregulation of pro-survival Bcl-2 and consequent chondrocyte anti-apoptosis. In terms of structural and histological outcomes, ESWT has been shown to enhance cartilage and ECM regeneration while alleviating synovitis in rat models of early KOA (137). These findings are corroborated by improvements in cartilage degradation and bone remodeling, as evidenced by reduced cartilage degradation and restored chondrocyte activity comparable with that of healthy controls (134).

Consistent with these structural observations, ESWT treatment in rat models resulted in changes in cartilage degradation biomarkers and type II collagen that were comparable to those of blank controls, while simultaneously upregulating subchondral bone remodeling markers such as VEGF, BMP-2 and osteocalcin (20,21,84,138). A further study in osteoporotic-associated KOA demonstrated that ESWT increased bone mineral density and bone strength, improved subchondral plate thickness, reduced excessive subchondral bone porosity and downregulated DKK-1 while elevating PCNA, VEGF and BMP-2 levels (139).

Beyond structural and molecular improvements, ESWT has also been associated with reduced chondrocyte apoptosis in rabbit models (19), as well as systemic proliferative and regenerative effects on cartilage in rat models (27,140). In addition, combination strategies have been explored: ESWT combined with adipose-derived mesenchymal stem cells increased the expression of TIMP-1 and type II collagen in a rat model of KOA (141), further supporting the potential of ESWT to promote ECM anabolism and restore the MMP/TIMP balance at the tissue level.

Cross-comparison of these in vivo studies reveals substantial heterogeneity in experimental design. Chou et al (137) and Wang et al (134) adopted rat OA models with different energy flux densities (0.18-0.25 mJ/mm2) targeting subchondral bone, whereas Zhao et al (19) utilized rabbit models and prioritized chondrocyte apoptosis detection as the primary readout. Such differences in animal species, OA induction protocols, ESWT energy parameters and detection indicators may lead to a variable magnitude of therapeutic effects across different studies, although no contradictory positive protective outcomes have been reported so far.

While the results observed in these studies were generally positive, several methodological limitations should be considered when interpreting this evidence. The observation period varied across studies; some reported results for 4-12 weeks, while others extended the observation period to 24 weeks, providing partial but incomplete evidence of long-term effects. Sample sizes ranged from 6 to 12 animals per group, with the larger studies providing greater statistical power, although the overall number of animals across all studies remains modest. In addition, the energy parameters and treatment protocols varied across the included studies, which complicates direct comparisons and makes it difficult to determine an optimal dosing regimen based on the current data. Notably, despite methodological variations, no major contradictory findings were observed across these studies, suggesting a generally consistent protective effect of ESWT across different experimental conditions. These considerations highlight the need for further standardization in preclinical study design, as well as for translational studies that bridge the gap between animal models and human KOA.

It is also important to distinguish between the structural modifications observed in animal models and the symptomatic improvements reported in human clinical trials. While the preclinical findings suggest potential disease-modifying properties at the structural level, the current evidence in human patients with KOA primarily supports symptomatic relief. Notably, high-quality human trials with serial arthroscopy or quantitative magnetic resonance imaging (MRI) to verify structural changes remain scarce, and there is currently insufficient clinical proof that ESWT induces measurable cartilage regeneration or joint space preservation in patients with KOA. Therefore, the structural effects observed in animal models should not be directly extrapolated to human clinical settings. With this distinction in mind, the following section reviews the clinical evidence for ESWT in KOA.

Effects of ESWT on KOA based on clinical studies

The clinical manifestations of KOA typically include persistent pain and physical functional limitations, which markedly impact patients' daily functioning and overall well-being. These persistent symptoms frequently make simple activities challenging. As an emerging treatment for KOA, ESWT has been proven by several studies to be safe and effective in improving knee pain and function in clinical settings (25,142-144). These positive effects can even persist for up to 12 months (145). Moreover, ESWT has been shown to be superior to physical therapy and placebo treatment in enhancing function and relieving pain, positioning it as an effective treatment option for KOA (50,146). Notably, the International Society for Medical Shockwave Treatment guidelines recommend f-ESWT for KOA, with parameters of 2,000-4,000 pulses at 0.25-0.6 mJ/mm2 applied to the femoral condyle and tibial plateau (147). However, the guidelines' recommendations do not necessarily imply that the other waveform type is without value; clinical responses may vary from patient to patient. For example, Imamura et al (148) found that r-ESWT was ineffective for patients with severe pain due to primary KOA, but the study also noted that increasing the energy settings in such cases might improve treatment outcomes. The lack of direct comparative studies precludes a definitive recommendation for one modality over the other in most clinical scenarios, and the choice should remain individualized based on the patient's specific pathological features, disease stage and treatment targets. The effects of ESWT on KOA in clinical studies are shown in Table II.

Table II Effect of ESWT on KOA in clinical studies.

Table II

Effect of ESWT on KOA in clinical studies.

Authors, year	Research object type	Dosage	Time post operation	Outcome	Conclusion	(Refs.)
Zhao et al, 2013	70 patients with primary KOA	EFD of 0.25 mJ/mm2 for 4,000 impulses.	4 times a week for 4 weeks.	VAS Score (pain on movement)↓, WOMAC score (pain, stiffness and limitations in physical function)↓, LI score (disability)↓, perception of clinical severity of OA↑	ESWT effectively reduces pain and improves knee function, having demonstrated superior efficacy to placebo during the 12-week treatment period.	(22)
Kim et al, 2015	60 patients with KOA	Low-energy group (n=30, 1,000 impulses/session, EFD/impulse 0.040 mJ/mm2) or medium-energy group (n=30, 1,000 impulses/session, EFD/impulse 0.093 mJ/mm2).	Once a week for 3 weeks.	VAS score↓, RM score (disability)↓, WOMAC score↓, LI score↓	Functional scores of both groups notably improved over time (P<0.001), with the medium-energy group improving more than the low-energy group.	(23)
Jhan et al, 2022	45 patients with KOA	EFD of 0.22 mJ/mm2 for 3,000 impulses.	Once every 2 weeks, a total of 3 times.	BMD↑, KOOS score (pain, symptoms, daily living activity ability, leisure and sports function, quality of life)↑, VAS score↓, WOMAC score↓	The pain relief effect of the ESWT group is better than that of the NSAIDs and HA groups.	(52)
Imamura et al, 2017	105 women with primary KOA	2,000 impulses per session, EFD of 0.10-0.16 mJ/mm2.	3 sessions, each 1 week apart.	VAS score↓, WOMAC score↓	Compared with placebo treatment, the ESWT group showed statistically significant improvement only in the WOMAC pain score on the treated side (P=0.038), with no significant difference in VAS score (P=0.132).	(148)
Lee et al, 2017	61 patients with KOA	EFD of 0.05 mJ/mm2 for 1,000 impulses.	3 times a week.	VAS score↓, WOMAC score↓, 40-meter fast-paced walk test completion time↓, 9-step SCT completion time↓, LI score↓	ESWT can be an alternative treatment for reducing pain and improving physical function in patients with KOA (P<0.01).	(168)
Li et al, 2018	105 patients with KOA	EFD of 0.11 mJ/mm2 for 3,000 impulses.	5 sessions with an interval of 3 days for a total of 12 weeks.	NRS score↓, WOMAC score (pain subscale)↓	Compared with laser therapy, ESWT showed greater relief effects on KOA symptoms in terms of NRS, WOMAC scores at 6 weeks (P<0.05) and 12 weeks (P<0.01) after treatment.	(155)
Lizis et al, 2017	40 patients with KOA	EFD of 0.4 mJ/mm2 for 800 impulses.	Once a week, a total of 5 times.	WOMAC score↓, ROM↑	ESWT is more effective than Kinesiotherapy in improving WOMAC and ROM in patients with KOA.	(175)
Zhong et al, 2019	63 patients with KOA	A total of 2,000 impulses of 8-Hz frequency at 2.5 bars.	Once a week for 4 consecutive weeks.	VAS score↓, WOMAC score↓, LI score↓	For patients with mild to moderate KOA, 4-week low-dose ESWT treatment is superior to placebo in relieving pain and improving function, but has some negative effects on joint cartilage.	(146)
Ko et al, 2022	42 patients with KOA	During each treatment session, 2,000 impulses are delivered at a frequency of 5 Hz. The intensities used during f-ESWT (0.10 mJ/mm2) and r-ESWT (3.0 bar) are comparable.	Receive 3 treatments, once every other week.	VAS score↓, WOMAC score↓, 6-min walk test↓	Both groups showed significant improvement over time (P<0.001); however, f-ESWT was more effective than r-ESWT in improving pain (VAS P=0.01) and physical function (WOMAC P<0.001 and 6-min walk test P=0.003).	(158)
Choi et al, 2023	18 patients with KOA	EFD of 0.05 mJ/mm2 total energy with 1,000 impulses.	Three times a week for 3 weeks.	VAS score↓, WOMAC score↓, LI score↓, joint effusion height↓	ESWT may be effective in reducing suprapatellar effusion and improving symptoms in mild KOA.	(144)
Zhang et al, 2021	89 patients with KOA	0.12 mJ/mm2, lower density, or 0.24 mJ/mm2, higher density.	Each group has 4 sessions every other week.	VAS score↓, WOMAC score↓	All treatment groups showed greater reductions in pain and WOMAC scores compared with the control group, and higher density may be more effective in relieving pain.	(164)
Xu et al, 2019	186 patients with severe KOA	2.0 bar, 0.25 mJ/mm2, and 8 Hz/sec.	Twice a week for 4 weeks continuously.	VAS score↓, WOMAC score↓, 50-meter rapid walking time↓	ESWT has the potential to alleviate pain and improve knee joint function, and the therapeutic effect may peak 8 weeks after the end of treatment.	(176)

[i] ↑, significant increase; ↓, significant decrease; ESWT, extracorporeal shock wave therapy; EFD, energy flux density; KOA, knee osteoarthritis; VAS, visual analogue scale; RM, Roles and Maudsley; LI, Lequesne index; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index; BMD, bone mineral density; NSAIDs, nonsteroidal anti-inflammatory drugs; HA, hyaluronic acid; ROM, range of motion; KOOS, Knee Outcome Survey; IKDC, International Knee Documentation Committee; SCT, stair-climb test; NRS, Numeric Rating Scale; f-ESWT, focused ESWT; r-ESWT, radial ESWT.

Pain

Relief of pain is regarded as a prerequisite for maintaining function and is a key factor influencing the healthcare-seeking behavior and treatment plans of patients with KOA (149,150). ESWT has been demonstrated to alleviate pain for KOA patients in clinical settings (25,49,143,145).

Systematic reviews/meta-analyses (SRs/MAs) represent highly valued clinical evidence, and high-quality SRs/MAs govern clinical practice (151). Multiple SRs/MAs have consistently demonstrated the safety and efficacy of ESWT in enhancing knee pain relief (50,142,143,152,153). Among these, the studies by Avendaño-Coy et al (153) underscore the superiority of ESWT over conventional or conservative treatments, as reflected by markedly lower pain scores on the visual analog scale (VAS) among patients receiving this intervention. Furthermore, the Grades of Recommendation Assessment, Development and Evaluation (GRADE) system (154) classifies ESWT as a 'moderate' recommendation, reinforcing its role as a viable therapeutic option within evidence-based practice. Yet, most SRs/MAs on ESWT for KOA rely on subjective measures when evaluating its effectiveness. However, these criteria are not consistently defined, which may introduce bias into the findings. Consequently, achieving widespread acceptance of the efficacy of the treatment on an international level is challenging. Most reviews focus solely on immediate outcomes, neglecting to account for the likelihood of relapse, which hinders the evaluation of the lasting effectiveness of ESWT. Furthermore, only a couple of studies touched upon potential side effects, yet both were lacking in comprehensive and standardized safety criteria and were solely concerned with efficacy, thereby restricting the applicability of the findings (142,153).

Supporting the SR/MA evidence, ESWT has been proven to have superior efficacy compared with NSAIDs in patients with KOA (52). A retrospective study conducted by Li et al (155) involving 105 patients with KOA provided compelling comparative data, wherein ESWT outperformed laser therapy in terms of pain reduction. Statistically significant improvements were observed at 6 weeks (P<0.05) and 12 weeks (P<0.01) post-treatment, as quantified by the Numerical Rating Scale (NRS) (156) and the pain subscales of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (157). A randomized controlled trial directly comparing f-ESWT and r-ESWT further found that f-ESWT produced greater reductions in VAS pain scores and greater improvements in WOMAC scores at the 4- and 8-week follow-up, suggesting superior efficacy in pain relief and functional improvement (158). Two randomized controlled trial (RCTs) confirmed the findings from animal model studies indicating that ESWT may be an effective treatment for disability-related pain caused by primary OA (22,23). Nevertheless, the included RCTs displayed differences in shock wave energy parameters, which may partly explain the variability in reported effect sizes. Excessive energy application may exacerbate KOA progression, whereas insufficient energy delivery can compromise treatment efficacy (135,159). In clinical practice, energy flux density (EFD) values typically range from 0.001 to 0.5 mJ/mm2 to minimize tissue damage (159-161), a range supported by experimental studies in rat models showing that EFDs >0.5 mJ/mm2 may induce cartilage deterioration (162). Clinical evidence suggests that higher energy levels are often associated with greater improvements in pain relief and functional outcomes compared with lower energy protocols (163,164), and multiple studies support the notion that increased energy delivery may enhance treatment efficacy (23,165). However, this relationship is not absolute. For example, Schofer et al (166) reported no marked difference in therapeutic efficacy between higher (0.78 mJ/mm2) and lower (0.33 mJ/mm2) energy levels in the treatment of tendinopathy when both exceeded an EFD threshold of 0.32 mJ/mm2. Furthermore, Liao et al (51) suggested that the cut-off point of EFD may influence the comparison of ESWT effects at different energy levels, which may help explain the inconsistency in previous findings. Moreover, most of these trials had notable methodological limitations, including a lack of double-blinding, a common challenge in ESWT research due to the difficulty of designing a credible sham-ESWT control that mimics the auditory and tactile sensations of active treatment without delivering therapeutic energy. Sample sizes were also relatively modest in some studies, which may limit statistical power and generalizability. In addition, adherence to the Consolidated Standards of Reporting Trials guidelines (167) was not consistently reported across the included trials, further constraining the transparency and reproducibility of the evidence.

While positive collective findings position ESWT as a promising therapeutic option, with evidence supporting pain relief in the short term and suggestive preclinical data for disease modification, further large-scale randomized, double-blind and multicenter clinical trials are needed to determine the optimal treatment parameters, long-term benefits and cost-effectiveness.

Function

Certain studies have established that ESWT can improve functional outcomes in patients with KOA, including joint range of motion and the ability to engage in physical activities (24,49,168). Multiple studies using standardized functional assessment tools, including the WOMAC, Lequesne index (169), Roles and Maudsley (170), Knee Outcome Survey (171) and International Knee Documentation Committee scores (172), have consistently reported favorable functional improvements following ESWT treatment (23,52,168). These benefits have been observed across various comparators, including placebo (22,173), NSAIDs and HA (52), and physical therapy controls (174,175), with GRADE evidence rated as 'moderate' (153). By contrast, studies have shown that r-ESWT actually delivers better results in improving the WOMAC functional scores than f-ESWT (51), suggesting that the choice of ESWT modality may influence functional outcomes. Such inconsistent outcomes suggest that the therapeutic advantage of either subtype varies according to the primary outcome measured, with f-ESWT superior for pain control and r-ESWT more favorable for global soft tissue-related functional recovery.

Notably, one study by Xu et al (176) extended the observation period to 6 months in 186 patients with severe KOA, using a 50-meter rapid walking test and gait analysis as objective functional measures. The study confirmed that ESWT alleviates knee pain and restores knee function, with treatment effects peaking at 8 weeks post-treatment. Xu et al (176) also noted an intriguing trend: Obese patients tend to respond more favorably to ESWT, demonstrating more pronounced therapeutic effects. This observation suggests that KOA is not solely linked to cartilage degeneration but may also stem from surrounding soft tissue involvement.

Collectively, these studies affirm ESWT as an effective intervention for mild-to-moderate KOA, offering functional restoration with a favorable safety profile (153). However, the long-term efficacy of ESWT remains understudied, particularly regarding its durability beyond the 6-month follow-up period observed in most trials. Additionally, the mechanisms underlying the differential response in obese patients warrant further exploration, as they may involve biomechanical factors, adipose-derived inflammatory mediators or altered load distribution in weight-bearing joints. Future research should be conducted in conjunction with advanced imaging techniques, such as dynamic MRI or ultrasound elastography, to assess structural changes in periarticular soft tissues following ESWT. Moreover, standardized protocols for treatment parameters, including EFD, frequency and number of sessions, are needed to optimize clinical outcomes and enable cross-study comparisons.

Conclusions and perspectives

As a chronic, disabling disease characterized primarily by pain and limited joint mobility, KOA has multiple etiologies and involves complex pathophysiological mechanisms (177). Among them, the progression of synovial inflammation, degradation of articular cartilage and abnormality of subchondral bone are the primary drivers of KOA development, which may eventually result in progressive and complete joint destruction (178,179). Prioritizing conservative treatment is the treatment principle for KOA (4). When other conservative approaches prove ineffective, ESWT frequently serves as a practical non-invasive alternative in clinical settings (180).

A noteworthy contribution to the safety research on ESWT comes from the experimental work by Renz and Rupp (181), which addresses long-standing concerns regarding potential chondrocyte toxicity. The findings suggest that previous studies using cell suspensions may not accurately reflect real-world conditions, as alginate cultures better mimic the natural viscoelastic environment of cartilage. Importantly, the investigators observed no cytotoxic effects on chondrocytes in these more physiologically relevant models following shockwave exposure. These findings substantially support the proposition that ESWT presents a favorable safety profile for articular tissues.

Mounting preclinical data suggests that ESWT may have disease-modifying potential in animal models, supporting its investigation as a non-invasive adjuvant therapy for KOA. Accumulating preclinical and clinical evidence demonstrates that ESWT relieves KOA-related symptoms and delays cartilage degeneration via diverse biological mechanisms (49,137). However, these structural effects have been consistently observed in preclinical models, whereas clinical evidence in humans primarily supports symptomatic relief, and high-quality trials confirming cartilage regeneration or joint space preservation remain limited. This non-invasive treatment appears to work through several key mechanisms, namely, reducing inflammation, inhibiting apoptosis, stimulating cell proliferation and maintaining cartilage homeostasis (19,23,85). Through these coordinated actions, ESWT may slow degenerative processes in preclinical models, while preclinical observations also suggest potential for activating reparative mechanisms, which may inform clinical investigations into pain and functional outcomes.

The EFD is crucial for effective ESWT treatment, with improper dosage potentially exacerbating KOA or reducing efficacy. The clinical range for EFD during ESWT treatment typically spans from 0.001 to 0.5 mJ/mm2 (159-161). However, research conducted using rat models has demonstrated that cartilage deterioration can occur at EFD levels exceeding 0.5 mJ/mm2, underscoring the need for dose regulation (162). The therapeutic potential of ESWT depends not only on energy delivery but also on the interaction between energy and the cellular environment. For instance, low-energy ESWT has been shown to induce a phenotypic shift in macrophages from the pro-inflammatory M1 polarization to the anti-inflammatory M2 polarization (68). This polarization shift is of particular interest as it may facilitate the resolution of inflammation and the promotion of tissue repair. By contrast, medium-to-high energy ESWT exerts its therapeutic effects by downregulating the expression of inflammatory mediators, thereby mitigating the inflammatory cascade and promoting cell proliferation (182). Existing clinical evidence indicates that moderate-energy ESWT may yield superior pain relief and functional recovery compared with low-energy protocols, with optimal energy settings varying according to KOA severity and disease stage (23). Considering these findings, it is important that further research be directed towards elucidating the complex molecular mechanisms underlying the therapeutic effects of ESWT. This includes a deeper understanding of the cellular and biochemical pathways that are activated or modulated by different EFD levels. Additionally, the optimization of ESWT parameter settings is crucial, as this will enable the precise tailoring of the therapeutic dose to the individual patient's needs. Furthermore, the timing of parameter application must be carefully considered, as the temporal dynamics of ESWT delivery can markedly impact the therapeutic outcome. Optimizing the precision and timing of ESWT delivery may maximize therapeutic benefits while minimizing potential risks.

Given its non-invasive property, acceptable safety performance and accumulating experimental evidence, ESWT can serve as a valuable adjunctive alternative within integrated KOA management protocols when conventional conservative treatments fail. Since clinicians rarely offer ESWT as monotherapy, future studies should evaluate more clinically tailored individualized regimens in terms of clinical efficacy. While current findings are encouraging, additional studies are needed to clarify its long-term effectiveness, ideal treatment protocols and biological mechanisms, research that will not only optimize therapeutic use but also provide a solid basis for future scientific inquiry in this area.

Availability of data and materials

Not applicable.

Authors' contributions

YC, SS and YZ designed the present manuscript. YC wrote the first draft of the manuscript. SS and YZ edited the manuscript. SW and JH performed the literature search and selected the studies to be analyzed. YC and CL were responsible for the figure preparation. YH contributed to the acquisition of funds. All authors critically revised the manuscript for important intellectual content and have read and approved the final manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Acknowledgments

Not applicable.

Funding

This research was funded by the Sichuan Provincial Administration of Traditional Chinese Medicine project 'Systematic Study on the Diagnosis and Treatment Rules of Knee Osteoarthritis in Traditional Chinese Medicine' (grant no. 25ZDAZX001) and the Sports Medicine Key Laboratory of Sichuan Province Project (grant no. 2025-A011).

References