Elsevier

Injury

Volume 45, Issue 3, March 2014, Pages 494-500
Injury

Comparison of the effects of dexketoprofen trometamol, meloxicam and diclofenac sodium on fibular fracture healing, kidney and liver: An experimental rat model

https://doi.org/10.1016/j.injury.2013.10.002Get rights and content

Abstract

Objectives

Nonsteroidal anti-inflammatory drugs (NSAIDs) are particularly used in patients with bone fractures, but there are limited studies on whether one NSAID is superior to another. In this study, we used histopathological and biochemical parameters to determine whether there are differences between the effects of the administration of clinical doses of dexketoprofen trometamol (DEXT), meloxicam (MEL) and diclofenac sodium (DIC) on the healing of closed fibular fractures and the toxicity of both the liver and kidney.

Methods

Twenty-eight male Sprague-Dawley rats were randomly divided into four groups of seven each. Closed diaphyseal fractures were formed in the left fibulas of all of the rats. The NSAIDs dexketoprofen trometamol (DEXT) (Arveles®), meloxicam (MEL) (Melox®) and diclofenac sodium (DIC) (Voltaren®) were intramuscularly administered to Groups I, II, and III, respectively, for a period of 10 days after the fibular fractures were performed. No pharmacological agents were administered to Group IV (Control group). Blood samples were collected from all of the rats after the fractures were performed, and the rats were sacrificed on day 28. The histopathological findings were compared, and the blood samples were evaluated to determine any differences between the levels of superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA).

Results

Our results suggest that DEXT and MEL impair the healing of bone fractures and that DIC does not histopathologically affect the healing process of bone fractures. We also found that DEXT, MEL, and DIC impaired the renal histopathology compared with the control group. However, the liver histopathological analysis showed that DEXT and MEL caused a higher degree of parenchymal necrosis compared with DIC.

Conclusion

Based on our results, DIC can be considered a relatively safe medication in patients with fractures.

Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) are especially useful in patients with bone fractures due to their excellent analgesic and anti-inflammatory effects. However, these drugs can significantly delay fracture healing [1], [2], [3], [4], [5], [6]. Endogenous prostaglandins (PGs), which are commonly found in bone, have beneficial effects on fracture healing [7], [8], [9], [10]. The effect of NSAIDs is focused on the inhibition of cyclooxygenase (COX). As a result of this inhibition, the PGs lose their effects as mediators in the bone fracture healing process [7], [11], [12]. However, in vitro studies have focused on the activity of osteoblasts and have shown that NSAIDs impair the bone turnover, regeneration, and proliferation of osteoblasts [13], [14], [15], [16]. There are limited studies on whether one NSAID shows superiority over another in the bone fracture healing process and with respect to kidney and liver toxicity [1], [17], [18], [19], [20], [21].

The aim of this study was to use histopathological and biochemical parameters to determine whether there are differences between the effects of the clinical dosages of dexketoprofen trometamol (DEXT), meloxicam (MEL), and diclofenac sodium (DIC) on the healing of closed fibular fractures with respect to toxicity of both the liver and kidney.

Section snippets

Materials and methods

The experimental protocols were approved by the institutional animal ethics committee. The animals were obtained from the medical and surgical experimental research centre of the institute. All of the rats were housed in polycarbonate cages in a room with controlled temperature (22 ± 2 °C) and humidity (50 ± 5%) and a 12-hour(h)/12-h light/dark cycle. The rats were fed laboratory pellet chow, and water was provided ad libitum. All of the following experiments followed the Guiding Principles for the

Fibular union histopathology

The histological scores of the DEXT and MEL study groups were significantly lower than those of the control group (p < 0.05). The scores of the DIC group were equal to those of the control group (p = 1.00). The comparison of the study groups revealed that all of the groups exhibited significant differences (DEXT-MEL, p < 0.05; DEXT-DIC, p < 0.05; and MEL-DIC, p < 0.05). The lowest scores were found in the MEL group. The histological scores and descriptive data are presented in Table 2, Table 3.

Discussion

Bone fracture healing is one of the most complex cascades of events that results to union [28]. Many factors, such as the use of NSAIDs for the prevention of bone fracture pain, can affect this process. Recent studies have shown that these drugs affect the process of bone fracture healing [29], [30], [31]. NSAIDs interfere with the arachidonic acid mechanism by blocking the formation of PGs through the inhibition of the cyclooxygenase pathway, which plays a fundamental role in the bone healing

Conclusion

At present, there is no strong scientific evidence that supports discarding of the use of NSAIDs for the treatment of fracture-related pain. Our results suggest that DEXT and MEL impair the bone fracture healing process. In contrast, DIC did not histopathologically affect the bone fracture healing process. Because our findings in rats should not be extrapolated to humans, there is a need for further studies on the effects of NSAIDs on the fracture healing process in humans.

In clinical

Conflict of interest statement

None declared.

References (50)

  • M. Weinreb et al.

    Systemic administration of an anabolic dose of PGE2 in young rats increases the osteogenic capacity of bone marrow

    Bone

    (1997)
  • B.C. Tiseo et al.

    Experimental study of the action of COX-2 selective nonsteroidal anti-inflammatory drugs and traditional anti-inflammatory drugs in bone regeneration

    Clinics (Sao Paulo)

    (2006)
  • H. de Groot et al.

    Ischemia-reperfusion injury: processes in pathogenetic networks: a review

    Transplant Proc

    (2007)
  • A.P. Geubel et al.

    Bile duct disorders

    Clin Liver Dis

    (2003)
  • G.P. Aithal et al.

    Nonsteroidal anti-inflammatory drug-induced hepatotoxicity

    Clin Liver Dis

    (2007)
  • I. Pountos et al.

    Do nonsteroidal anti-inflammatory drugs affect bone healing? A critical analysis

    ScientificWorldJournal

    (2012)
  • G.D. Krischak et al.

    Effects of diclofenac on periosteal callus maturation in osteotomy healing in an animal model

    Arch Orthop Trauma Surg

    (2007)
  • D. Kaspar et al.

    Diclofenac inhibits proliferation and matrix formation of osteoblast cells

    Unfallchirurg

    (2005)
  • G. Matziolis et al.

    Modification of human osteoblasts by various analgesics

    Unfallchirurg

    (2002)
  • S. Sells et al.

    Effect of diclofenac on human osteoblasts and their stromal precursors in vitro in relation to arthroplasty

    Z Rheumatol

    (1999)
  • A. Beck et al.

    Influence of diclofenac (group of nonsteroidal anti-inflammatory drugs) on fracture healing

    Arch Orthop Trauma Surg

    (2003)
  • H. Kawaguchi et al.

    The role of prostaglandins in the regulation of bone metabolism

    Clin Orthop Relat Res

    (1995)
  • S. Dekel et al.

    Release of prostaglandins from bone and muscle after tibial fracture An experimental study in rabbits

    J Bone Joint Surg Br

    (1981)
  • J.R. Vane

    Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs

    Nature New Biol

    (1971)
  • G.D. Krischak et al.

    The non-steroidal anti-inflammatory drug diclofenac reduces appearance of osteoblasts in bone defect healing in rats

    Arch Orthop Trauma Surg

    (2007)
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