Pain Neuropeptides CGRP and Substance P Increase in Ankle Osteoarthritis Bone as Cartilage Degenerates

Seventeen ankles from 16 patients who underwent total ankle arthroplasty for OA were analyzed. Researchers conducted radiographic evaluation, CT imaging with Hounsfield unit measurements, and histologic analysis including subchondral bone plate thickness and trabecular bone area measurements. Cartilage degeneration was scored using modified Mankin criteria. Immunohistochemistry was performed for CGRP, substance P, collagen types I, II, and X, and TRAP staining identified osteoclasts. Correlations between neuropeptide expression and structural/degenerative parameters were analyzed.

This is the first study to systematically map neuropeptide expression in subchondral bone specifically in ankle OA, revealing that the bone itself — not just the joint lining or cartilage — is a source of pain-related neuropeptides. The finding that CGRP appears before substance P suggests it may serve as an earlier biomarker or therapeutic target. The link between neuropeptides and osteoclast activity opens the possibility that pain signaling and bone destruction are mechanistically connected, not just coincidental.

This study adds important evidence to the emerging understanding that OA is not just a cartilage disease — the subchondral bone plays an active role in both structural damage and pain generation. The neuropeptides CGRP and substance P, already targets of breakthrough therapies for migraine, may represent treatable pathways in OA as well. The connection between neuropeptide expression and osteoclast activity suggests that pain and bone destruction may share common signaling mechanisms, potentially allowing single therapies to address both.

This is a cross-sectional study, meaning it captures one timepoint and cannot establish whether neuropeptide upregulation causes or results from bone changes and cartilage degeneration. The sample size is small (17 ankles from 16 patients). All specimens came from end-stage OA requiring arthroplasty, so findings may not represent earlier disease stages. The study is specific to ankle OA and may not generalize to hip or knee OA. Quantitative neuropeptide measurements were not performed — only immunohistochemical staining patterns.