β₂-Adrenergic receptor antagonists are not protective against spinal cord injury-induced bone loss.

Abstract

Bone loss is an underestimated consequence of spinal cord injury (SCI), that manifests rapidly and is resistant to currently available treatments including exercise, functional electrical stimulation, anabolic agents, and bisphosphonates. While changes in adrenergic signaling have been linked to bone loss, it remains unclear whether maladaptive sympathetic signaling drives SCI-induced bone loss. We evaluated the effects of sympathetic blockade on SCI-induced bone loss using primary bone marrow osteoclast cultures and an in vivo rat model of a moderate T11 spinal contusion injury using young (300-350 g) male Sprague Dawley rats. In vitro, pre-osteoclast formation was significantly elevated in SCI cultures compared to shams, and exogenous norepinephrine (NE) robustly enhanced this effect. Concomitant administration of adrenergic receptor (AR) antagonists, with varying α- and β-AR selectivity, completely attenuated this NE-driven osteoclastogenesis. Moving in vivo, we utilized a novel intraosseous catheter for targeted delivery of labetalol (mixed α- and β-AR antagonist) and butoxamine (selective β-AR antagonist) directly into the sublesional (below the level of injury) bone marrow space for 28 consecutive day, beginning 24 h post-injury. Analysis of the femur microarchitecture from both legs revealed that blocking local sympathetic signaling failed to protect trabecular bone after SCI. Furthermore, while both labetalol and butoxamine had no effect on locomotor recovery, post-injury weight loss was increased compared to saline-treated SCI controls. These findings demonstrate that while blocking β₂-ARs is sufficient to reduce NE-driven osteoclastogenesis, excessive NE does not fully explain SCI-induced bone loss. Local AR antagonists do not appear to be a viable therapeutic strategy to mitigate SCI-induced osteoporosis.