Work

Pulsed radiofrequency neuromodulation of subchondral bone in knee osteoarthritis

Year: 2026

Type: article

Abstract: Bone marrow lesions (BMLs) on magnetic resonance imaging (MRI) are associated with pain and structural progression in knee osteoarthritis (OA), yet no approved therapy targets the subchondral bone compartment with a demonstrated structural effect. We hypothesize that a pulsed radiofrequency (PRF) electrode positioned percutaneously within the subchondral trabecular bone of the medial tibial plateau may modulate a local sensory nerve-osteoclast-osteoblast circuit that sustains the BML, reducing both pain and lesion volume. The rationale combines four observations, most of them obtained in settings other than human OA. First, subchondral bone is innervated by peptidergic sensory fibers, which in human OA accompany vascular channels across the osteochondral junction, and in murine OA, osteoclasts induce sensory nerve growth into subchondral bone. Second, in genetic mouse models, sensory nerve ablation reduces bone volume and sensory knockout of EP4 or TrkA attenuates load-induced bone formation. Third, a PRF electrode generates electric fields of the order of hundreds of V/cm within millimeters of its tip, at least four orders of magnitude above the fields of 0.07 to about 2 mV/cm induced in bone-cell studies of pulsed electromagnetic fields (PEMF); the benchmark electroporation threshold comes from a non-neuronal cell line and requires bone-specific validation. Fourth, one uncontrolled series of ten patients with femoral head osteonecrosis shows that intraosseous PRF electrode placement is technically feasible, but it reported neither pain scores nor adverse-event data and does not establish safety. We specify a staged program: bone-specific electrothermal modeling and ex vivo dosimetry; a randomized, blinded, sham-controlled study in the murine destabilization of the medial meniscus model with functional neuronal readouts and targeted sensory denervation; large-animal dosimetry; and a human feasibility study followed by an external pilot randomized trial using quantitative BML volumetry. Prespecified predictions define success, failure, and inconclusive results. The nerve growth factor (NGF)-TrkA axis, the proposed mediator, carries an internal paradox: NGF appears reparative in necrotic bone but sensitizing in osteoarthritic joints, and anti-NGF treatment relieves OA pain while worsening subchondral bone and cartilage in an animal model. Determining which effect predominates is the central test of this proposal.

Source: Frontiers in Pain Research

DOI: 10.3389/fpain.2026.1968444