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Parameters for Lithium Treatment Are Critical in Its Enhancement of Fracture-Healing in Rodents

Bernick, Joshua MSc; Wang, Yufa MSc, MD; Sigal, Ian A. PhD; Alman, Benjamin A. MD; Whyne, Cari M. PhD; Nam, Diane MSc, MD

Journal of Bone & Joint Surgery - American Volume: 3 December 2014 - Volume 96 - Issue 23 - p 1990–1998
doi: 10.2106/JBJS.N.00057
Scientific Articles
Supplementary Content

Background: Lithium, a treatment for bipolar disorder, is not clinically indicated for use in fracture management but has been reported to positively influence bone biology. It is hypothesized that lithium dosing for beneficial effects on bone health may be much lower than the dosing required for psychotropic benefits in patients with bipolar disorder. A preclinical study with a rodent fracture model was utilized to best define the lowest effective dose, best timing of treatment onset, and optimal treatment duration for the use of lithium as a new treatment in fracture care.

Methods: A design-of-experiments approach was used to assess the parameters of dose, timing of treatment onset, and treatment duration. Closed femoral shaft fractures were generated and analyzed with use of destructive torsional mechanical testing and microcomputed tomography-based image analysis. Eleven different outcome measures were quantified, with maximum yield torque as the primary study outcome, to assess the quality of long-bone fracture-healing.

Results: Fracture-healing was maximized with a lithium treatment combination of a low dose (twenty milligrams per kilogram of body weight per day), later onset of lithium treatment (seven days after fracture), and longer treatment duration (two weeks), with maximum yield torque displaying a 46% increase compared with nontreated and sham-treated controls (481.1 ± 104.0 N-mm compared with 329.9 ± 135.8 N-mm; p = 0.04). Design-of-experiments analysis determined the timing of treatment onset to be the most influential parameter for improving fracture-healing, with femora treated at a later onset (seven days after fracture) showing a significant (21%) increase in maximum yield torque compared with those treated at an earlier onset (three days after fracture) (p = 0.01).

Conclusions: A later onset of lithium administration significantly improved femoral fracture-healing. Trends indicated that a lower dose and longer treatment duration also had a positive effect on fracture repair.

Clinical Relevance: Orally administered low-dose lithium therapy with a large postfracture administration window has the potential to yield a safe, reliable, and cost-effective treatment to enhance bone-healing and restore earlier function and mobility pending appropriate large-animal proof-of-concept models, safety data, and U.S. Food and Drug Administration clinical trials approval.

1Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, MG361, Toronto, ON, M4N 3M5, Canada. E-mail address for D. Nam:

2Ocular Biomechanics Laboratory, University of Pittsburgh School of Medicine, 203 Lothrop Street, Room 930, Pittsburgh, PA 15213. E-mail address:

3Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada. E-mail address:

Copyright 2014 by The Journal of Bone and Joint Surgery, Incorporated
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