Low-dose lithium regimen enhances endochondral fracture healing in osteoporotic rodent bone.

Abstract

Osteoporotic bone fractures are highly prevalent and involve lengthy recovery. Lithium, commonly used in psychiatric medicine, inhibits glycogen synthase kinase-3β in the Wnt/β-catenin pathway, leading to up-regulation of osteogenesis. Our recent preclinical work demonstrated that a 20 mg/kg lithium dose administered beginning 7 days post-fracture for 14 days optimally improved femoral fracture healing in healthy rats at 4 weeks post fracture (46% higher torsional strength). In this study, lithium treatment was evaluated for healing of osteoporotic bone fractures. Six-month-old ovariectomized rats were subjected to closed, load-drop induced femoral diaphyseal fracture. Two regimens involving treatment initiation on day 7 and day 10, respectively, 20 mg/kg/day oral dose and 14 days duration were evaluated. Femurs of lithium- vs. saline- treated rats were analyzed at 4 weeks (for day 7 onset regimen) or 6 weeks (for day 10 onset regimen) post-fracture by stereology and torsional mechanical testing. Initiation on day 10 led to a significant 50% higher maximum yield torque (primary outcome measure) at 6 weeks (309 vs. 206 N-mm, p = 0.005; n = 7, 7). Initiation on day 7 suggested a trend toward a more modest improvement in maximum yield torque (13%) evaluated at 4 weeks post-fracture (234 vs. 206 N-mm, p = 0.10; n = 10, 13). Qualitatively, lithium-treated femurs demonstrated better periosteal and mineralized callus bridging in the day 10 initiation group. Lithium is a widely-available, orally administered, low-cost drug, which represents a feasible pharmacological intervention for both healthy and osteoporotic fracture healing. This study provides important guidelines for future clinical evaluation of lithium in osteoporotic fracture patients. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1783-1789, 2018.

• Authors: Kathak Vachhani, Cari Whyne, Yufa Wang, David M Burns, Diane Nam
• Journal: Journal of orthopaedic research : official publication of the Orthopaedic Research Society (J Orthop Res) Vol. 36 Issue 6 Pg. 1783-1789 (06 2018) ISSN: 1554-527X [Electronic] United States
• PMID: 29106746 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Chemical References

• Lithium

Topics

• Animals
• Female
• Femoral Fractures (drug therapy, physiopathology)
• Fracture Healing (drug effects)
• Lithium (pharmacology, therapeutic use)
• Osteoporotic Fractures (drug therapy, physiopathology)
• Rats
• Rats, Sprague-Dawley
• Torsion, Mechanical
• X-Ray Microtomography