Design of experiments confirms optimization of lithium administration parameters for enhanced fracture healing.

Abstract

Fracture healing is a lengthy process which fails in 5-10% of cases. Lithium, a low-cost therapeutic used in psychiatric medicine, up-regulates the canonical Wingless pathway crucial for osteoblastic mineralization in fracture healing. A design-of-experiments (DOE) methodology was used to optimize lithium administration parameters (dose, onset time and treatment duration) to enhance healing in a rat femoral fracture model. In the previously completed first stage (screening), onset time was found to significantly impact healing, with later (day 7 vs. day 3 post-fracture) treatment yielding improved maximum yield torque. The greatest strength was found in healing femurs treated at day 7 post fracture, with a low lithium dose (20 mg/kg) for 2 weeks duration. This paper describes the findings of the second (optimization) and third (verification) stages of the DOE investigation. Closed traumatic diaphyseal femur fractures were induced in 3-month old rats. Healing was evaluated on day 28 post fracture by CT-based morphometry and torsional loading. In optimization, later onset times of day 10 and 14 did not perform as well as day 7 onset. As such, efficacy of the best regimen (20 mg/kg dose given at day 7 onset for 2 weeks duration) was reassessed in a distinct cohort of animals to complete the DOE verification. A significant 44% higher maximum yield torque (primary outcome) was seen with optimized lithium treatment vs. controls, which paralleled the 46% improvement seen in the screening stage. Successful completion of this robustly designed preclinical DOE study delineates the optimal lithium regimen for enhancing preclinical long-bone fracture healing.

• Authors: Kathak Vachhani, Andrea Pagotto, Yufa Wang, Cari Whyne, Diane Nam
• Journal: Journal of biomechanics (J Biomech) Vol. 66 Pg. 153-158 (01 03 2018) ISSN: 1873-2380 [Electronic] United States
• PMID: 29162229 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• Lithium Chloride

Topics

• Animals
• Female
• Femoral Fractures (drug therapy, physiopathology)
• Fracture Healing (drug effects)
• Lithium Chloride (therapeutic use)
• Rats, Sprague-Dawley
• Torque