Ketorolac administration does not delay early fracture healing in a juvenile rat model: a pilot study

Abstract

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective at controlling pain in children, especially in the treatment of fractures. Adult animal and adult clinical studies demonstrate conflicting evidence for the inhibitory relationship between NSAIDs and fracture healing. Published pediatric orthopaedic clinical studies do not demonstrate an inhibitory effect of ketorolac on bone healing. Little is known about the effects of any NSAID on bone formation in juvenile animals. This study investigates the effects of the NSAID ketorolac on fracture healing in a juvenile rat model.

Methods: Unilateral surgically induced and stabilized tibial shaft fractures were created in 45 juvenile (3 to 4 wk old) male Sprague-Dawley rats. Either ketorolac (5 mg/kg; n=24) or saline (0.9% normal saline; n=21) was then administered to the rats 6 d/wk by intraperitoneal injections. Animals were then randomly assigned into time groups and euthanized at 7 days (n=8 ketorolac, n=7 saline), 14 days (n=8 ketorolac, n=7 saline), or 21 days (n=8 ketorolac, n=7 saline) postfracture. Biomechanical analysis was performed using a custom-designed 4-point bending loading apparatus. Statistics for tibial stiffness and strength data were performed using software package Systat 11. Specimens were also evaluated histologically using hematoxylin and eosin staining.

Results: Strength and stiffness of all fractured tibiae increased over time from day 7 to day 21 regardless of treatment type. No statistical difference was found between the fractured tibiae strength or stiffness in the ketorolac or control-treated specimens at the same time point. In addition, the quality of the fracture callus was similar in both groups at each of the time points.

Conclusions: In this study of a juvenile rat model with a stabilized tibia fracture, fracture callus strength, stiffness, and histologic characteristics were not affected by the administration of ketorolac during the first 21 days of fracture healing.

Clinical relevance: The absence of inhibitory effects of ketorolac on early juvenile rat fracture healing supports the clinical practice of utilizing NSAIDs for analgesia in children with long bone fractures.

FIGURE 1

Fractured tibiae strength. Strength, measured by maximum compression in Newtons, of the fractured saline control groups and the fractured ketorolac treatment groups at each time point.

FIGURE 2

Fractured tibiae stiffness. Stiffness, measured in Newtons per millimeter, of the fractured saline control groups and ketorolac groups at each time point.

FIGURE 3

Fractured tibiae versus contralateral tibiae strength at day 21. Neither the saline control nor the ketorolac fractured tibiae reached full strength by day 21 postfracture compared with the contralateral nonfractured tibiae.

FIGURE 4

Images of hematoxylin and eosin-stained specimens of the fractured tibiae at each time point comparing the saline control groups and ketorolac treatment groups. Hypertrophied chondrocytes (arrows in A and B) at day 7; woven bone at day 14 (C and D); further woven bone and early compact lamellar bone (arrows in E and F) at day 21.