Short-term perioperative parecoxib is not detrimental to shaft fracture healing in a rat model

Abstract

Objectives: Experimental studies indicate that non-steroidal anti-inflammatory drugs (NSAIDs) may have negative effects on fracture healing. This study aimed to assess the effect of immediate and delayed short-term administration of clinically relevant parecoxib doses and timing on fracture healing using an established animal fracture model.

Methods: A standardized closed tibia shaft fracture was induced and stabilized by reamed intramedullary nailing in 66 Wistar rats. A 'parecoxib immediate' (Pi) group received parecoxib (3.2 mg/kg bodyweight twice per day) on days 0, 1, and 2. A 'parecoxib delayed' (Pd) group received the same dose of parecoxib on days 3, 4, and 5. A control group received saline only. Fracture healing was evaluated by biomechanical tests, histomorphometry, and dual-energy x-ray absorptiometry (DXA) at four weeks.

Results: For ultimate bending moment, the median ratio between fractured and non-fractured tibia was 0.61 (interquartile range (IQR) 0.45 to 0.82) in the Pi group, 0.44 (IQR 0.42 to 0.52) in the Pd group, and 0.50 (IQR 0.41 to 0.75) in the control group (n = 44; p = 0.068). There were no differences between the groups for stiffness, energy, deflection, callus diameter, DXA measurements (n = 64), histomorphometrically osteoid/bone ratio, or callus area (n = 20).

Conclusion: This study demonstrates no negative effect of immediate or delayed short-term administration of parecoxib on diaphyseal fracture healing in rats.Cite this article: G. A. Hjorthaug, E. Søreide, L. Nordsletten, J. E. Madsen, F. P. Reinholt, S. Niratisairak, S. Dimmen. Short-term perioperative parecoxib is not detrimental to shaft fracture healing in a rat model. Bone Joint Res 2019;8:472-480. DOI: 10.1302/2046-3758.810.BJR-2018-0341.R1.

Keywords: Biomechanical; Cyclooxygenase inhibitors; Fracture healing; Histology; Rats.

Fig. 1

Three-point loading fracture forceps secured in a vice (V). Photo from the pilot study using bone without soft tissue, showing the components of the nail: the stylus (S); and the two cannulas (C). In vivo, the heel was pressed against an adjustable plate (P) in order to obtain a standardized midshaft fracture as the wedge (W) pressed the leg into the groove (G) when the forceps was clamped.

Fig. 2

Lateral-view photographs of tibia ex vivo at four weeks of healing. Orientation is proximal (P) to distal (D). a) Fractured (F) and non-fractured (NF) tibia from a specimen (‘parecoxib immediate’ (Pi) group) prepared for biomechanical tests. b) Segment of middle tibia containing callus in a specimen (control group) fixed for histological analysis.

Fig. 3

High-power magnification light microscopy of tibial fracture calluses. Masson–Goldner trichrome staining of mineralized tissue provides good differentiation between osteoid (O, purple) and mineralized bone matrix (MdB, green). Non-mineralized bone marrow (BMa, red) is distributed between the mineralized bone trabeculae. a) Woven bone formation (control group) with mainly osteoid trabecular surfaces (OS) and a few bone surfaces (BS). b) An immature region within the callus-containing cartilage (Cg) and partly mineralized matrix with ongoing endochondral ossification. Scale bars = 200 μm.

Fig. 4

Representative lateral radiograph at baseline showing a short oblique tibial fracture (large arrows) fixed with an intramedullary nail and concomitant fibular fracture (small arrow). Specimen from the control group.

Fig. 5

Low-power magnification light microscopy of Masson–Goldner trichrome-stained coronal section of diaphyseal (Dp) tibial fracture (between large arrows) at four weeks (‘parecoxib immediate’ (Pi) group), showing bridging callus formation on both sides. Callus consists of woven bone (Wo) and immature cartilage (Cg). The metaphyseal (Mt) region in the section is localized proximally. Small arrows indicate the original cortical fracture gap. The medullary canal contains displaced bone marrow (Ma). The clear space represents the area of the extracted nail. The rectangle shows the area displayed at high magnification in Figure 3b. Scale bar = 2 mm.

Fig. 6

Low-power (left panels) and high-power (right panels) magnification light microscopy of representative Masson–Goldner trichrome-stained sections of tibial fractures from the three study groups. Qualitatively, no differences between the study groups were observed. Scale bars = 2 mm (left panels) and 200 μm (right panels).