The selective norepinephrine reuptake inhibitor reboxetine promotes late-stage fracture healing in mice

Antonia Donat; Shan Jiang; Weixin Xie; Paul Richard Knapstein; Lilly-Charlotte Albertsen; Judith Luisa Kokot; Jan Sevecke; Ruben Augustin; Denise Jahn; Timur Alexander Yorgan; Karl-Heinz Frosch; Serafeim Tsitsilonis; Anke Baranowsky; Johannes Keller

doi:10.1016/j.isci.2023.107761

The selective norepinephrine reuptake inhibitor reboxetine promotes late-stage fracture healing in mice

iScience. 2023 Aug 29;26(10):107761. doi: 10.1016/j.isci.2023.107761. eCollection 2023 Oct 20.

Authors

Antonia Donat¹, Shan Jiang¹, Weixin Xie¹, Paul Richard Knapstein¹, Lilly-Charlotte Albertsen¹, Judith Luisa Kokot¹, Jan Sevecke¹, Ruben Augustin¹, Denise Jahn^{2

3}, Timur Alexander Yorgan⁴, Karl-Heinz Frosch^{1

5}, Serafeim Tsitsilonis^{2

3}, Anke Baranowsky¹, Johannes Keller¹

Affiliations

¹ Department of Trauma and Orthopedic Surgery, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
² Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, Germany.
³ Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, 13353 Berlin, Germany.
⁴ Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
⁵ Department of Trauma Surgery, Orthopedics and Sports Traumatology, BG Hospital Hamburg, 21033 Hamburg, Germany.

Abstract

Impaired fracture healing is of high clinical relevance, as up to 15% of patients with long-bone fractures display non-unions. Fracture patients also include individuals treated with selective norepinephrine reuptake inhibitors (SNRI). As SNRI were previously shown to negatively affect bone homeostasis, it remained unclear whether patients with SNRI are at risk of impaired bone healing. Here, we show that daily treatment with the SNRI reboxetine reduces trabecular bone mass in the spine but increases cortical thickness and osteoblast numbers in the femoral midshaft. Most importantly, reboxetine does not impair bone regeneration in a standardized murine fracture model, and even improves callus bridging and biomechanical stability at late healing stages. In sum, reboxetine affects bone remodeling in a site-specific manner. Treatment does not interfere with the early and intermediate stages of bone regeneration and improves healing outcomes of the late-stage fracture callus in mice.

Keywords: Cellular physiology; Injury; Treatment.