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Parameters for lithium treatment are critical in its enhancement of fracture-healing in rodents.

Publication ,  Journal Article
Bernick, J; Wang, Y; Sigal, IA; Alman, BA; Whyne, CM; Nam, D
Published in: J Bone Joint Surg Am
December 3, 2014

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.

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Published In

J Bone Joint Surg Am

DOI

EISSN

1535-1386

Publication Date

December 3, 2014

Volume

96

Issue

23

Start / End Page

1990 / 1998

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Torque
  • Rats, Sprague-Dawley
  • Rats
  • Protein Kinase Inhibitors
  • Orthopedics
  • Lithium
  • Fractures, Closed
  • Fracture Healing
  • Femoral Fractures
 

Citation

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Bernick, J., Wang, Y., Sigal, I. A., Alman, B. A., Whyne, C. M., & Nam, D. (2014). Parameters for lithium treatment are critical in its enhancement of fracture-healing in rodents. J Bone Joint Surg Am, 96(23), 1990–1998. https://doi.org/10.2106/JBJS.N.00057
Bernick, Joshua, Yufa Wang, Ian A. Sigal, Benjamin A. Alman, Cari M. Whyne, and Diane Nam. “Parameters for lithium treatment are critical in its enhancement of fracture-healing in rodents.J Bone Joint Surg Am 96, no. 23 (December 3, 2014): 1990–98. https://doi.org/10.2106/JBJS.N.00057.
Bernick J, Wang Y, Sigal IA, Alman BA, Whyne CM, Nam D. Parameters for lithium treatment are critical in its enhancement of fracture-healing in rodents. J Bone Joint Surg Am. 2014 Dec 3;96(23):1990–8.
Bernick, Joshua, et al. “Parameters for lithium treatment are critical in its enhancement of fracture-healing in rodents.J Bone Joint Surg Am, vol. 96, no. 23, Dec. 2014, pp. 1990–98. Pubmed, doi:10.2106/JBJS.N.00057.
Bernick J, Wang Y, Sigal IA, Alman BA, Whyne CM, Nam D. Parameters for lithium treatment are critical in its enhancement of fracture-healing in rodents. J Bone Joint Surg Am. 2014 Dec 3;96(23):1990–1998.

Published In

J Bone Joint Surg Am

DOI

EISSN

1535-1386

Publication Date

December 3, 2014

Volume

96

Issue

23

Start / End Page

1990 / 1998

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Torque
  • Rats, Sprague-Dawley
  • Rats
  • Protein Kinase Inhibitors
  • Orthopedics
  • Lithium
  • Fractures, Closed
  • Fracture Healing
  • Femoral Fractures