. 2026 Aug 10;19:629190. doi: 10.2147/IJGM.S629190

Table 1.

Evidence Hierarchy and Interpretive Boundaries for ESWT-Related Neuroimmune and Matrix-Metabolic Effects in Knee Osteoarthritis

Evidence Domain	Key evidence and Mechanistic Implication	Interpretive Boundary
Clinical symptomatic efficacy	Randomized trials and meta-analyses consistently support reductions in pain and improvements in function after ESWT.^15–20^,⁶⁹ These findings establish clinical relevance and show that treatment response is parameter dependent.	The evidence supports symptomatic benefit, but pain and functional improvement do not demonstrate cartilage regeneration or disease modification.
Human biochemical evidence in KOA	Serum MMP-3 and selected synovial inflammatory, oxidative, or matrix-metabolic markers may improve after ESWT or ESWT-based combined therapy.⁶⁸^,⁷⁰^,⁷¹ This suggests modulation of the joint catabolic microenvironment.	Small samples, circulating biomarkers, and combined interventions limit attribution to ESWT alone; biomarker change is not equivalent to structural protection.
KOA animal matrix-metabolic evidence	KOA models report lower MMP-1/3 or MMP-13/ADAMTS-5, higher TIMP-1, reduced IL-1β, TNF-α, and NO, and improved cartilage or subchondral-bone findings after ESWT.^73–77 The results support regulation of inflammation, oxidative stress, and the MMP/ADAMTS–TIMP network.	The findings are preclinical and vary by species, model, target site, and dose; they cannot establish patient-level structural modification.
Neurogenic inflammation and pain modulation	KOA and non-KOA models indicate that ESWT can alter sensory nerve input and SP/CGRP-related signaling, with accompanying changes in pain behavior or DRG neuropeptide markers.^81–87 This supports reduced neural excitability and neuroimmune amplification as plausible analgesic mechanisms.	Much of the neural evidence is non-KOA or animal based; structural nerve-fiber effects should not be assumed in patients receiving routine clinical protocols.
Structural modification and disease progression	Animal studies show cartilage, synovial, and subchondral-bone changes after ESWT, particularly when treatment is directed to the subchondral bone.^75–77^,⁹⁰ These observations provide biological plausibility for matrix-modulatory effects.	Human studies rarely include longitudinal MRI, cartilage-thickness measures, cleavage products, or progression endpoints; disease-modifying efficacy remains unproven.
Shared signaling and temporal coupling	IL-1β, TNF-α, NF-κB, and MAPK may connect neuroimmune amplification with MMP/ADAMTS transcription. Analgesic effects may emerge earlier than matrix-related changes.^45–48^,⁵³^,^88–90 This provides the rationale for the proposed dual-pathway framework.	The coupling and temporal sequence are cross-study inferences and require longitudinal, multi-endpoint, pathway-directed validation within the same model or cohort.

Notes: Evidence domains indicate source and directness rather than formal certainty grading. Interpretive boundaries identify limits of causal inference and distinguish symptomatic improvement from unconfirmed structural modification.

Abbreviations: ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; CGRP, calcitonin gene-related peptide; DRG, dorsal root ganglion; ESWT, extracorporeal shock wave therapy; IL-1β, interleukin-1β; KOA, knee osteoarthritis; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; NF-κB, nuclear factor-κB; NO, nitric oxide; SP, substance P; TIMP, tissue inhibitor of metalloproteinases; TNF-α, tumor necrosis factor-α.