Abstract
Predictable fracture healing fails to occur in 5–10% of cases. This is particularly concerning among individuals with osteoporosis. With an increasing aging population, one in three women and one in five men above the age of 50 experience fragility fractures. As such, there is a critical need for an effective treatment option that could enhance fracture healing in osteoporotic bone. Lithium, the standard treatment for bipolar disorder, has been previously shown to improve fracture healing through modulation of the Wnt/beta-catenin pathway. We optimised the precise oral lithium administration parameters to improve mechanical strength and enhance healing of femoral fractures in healthy rats. A low dose of Lithium (20 mg/kg) administered seven days post fracture for a two week duration improved torsional strength by 46% at four weeks post fracture compared to non-treated animals. Application of lithium to enhance fracture healing in osteoporotic bone would have a significant healthcare impact and requires further study. Aim: To evaluate the efficacy of optimal lithium administration post fracture on quality of fracture healing in a rat osteoporotic model. Hypothesis: Lithium treatment in osteoporotic rats will improve the structural and mechanical properties of the healing bone despite the impaired nature of bone tissue.
Sprague Dawley female rats (∼350 g, age ∼3 months) were bilaterally ovariectomised and maintained for 3 months to establish the osteoporotic phenotype. A unilateral, closed mid-shaft femoral fracture was created using a weight-drop apparatus. At seven days post fracture, the treatment group received 20 mg/kg-wt lithium chloride via oral gavage daily for 14 days. The control group received an equivalent dose of saline. All animals were sacrificed at day 28 and the femurs harvested bilaterally. Treatment efficacy was evaluated based on torsional loading and stereologic analysis.
Lithium treatment positively impacted the healing femurs, with an average yield torque ∼1.25-fold higher than in the saline group (200±36 vs. 163±31 N-mm, p=0.15). Radiographically, the lithium-treated rats had a high level of restored periosteal continuity, larger bridging and intercortical callus at the fracture site. These hallmarks of healing were generally absent in the saline group. The Lithium group had significantly higher total volume (624±32 vs. 568±95 mm3), lower bone volume fraction (41±4 vs. 50±5%) and higher theoretical torsional rigidity (477±50 vs. 357±93 kN-mm2) compared to the saline group. Torsional strength and stereology values were similar for the contralateral femurs of the two groups.
Lithium was found to enhance fracture healing in osteoporotic bone under the dosing regimen optimised in healthy femora. This is promising data as treatment represents an easily translatable pharmacological intervention for fracture healing that may ultimately reduce the healthcare burden of osteoporotic fractures.
