Research article
Impact of NSAID etoricoxib on side effects of orthodontic tooth movement

https://doi.org/10.1016/j.aanat.2020.151585Get rights and content

Abstract

Objectives

The non-steroidal anti-inflammatory drug etoricoxib is the most highly selective inhibitor of cyclooxygenase-2 available (344:1) and has been approved for postoperative pain therapy following dental interventions in Europe. At clinically relevant doses it has been reported to only have marginal effects on the velocity of orthodontic tooth movement (OTM). Its effects on associated dental root resorptions, osteoclastogenesis, trabecular number in the alveolar bone and periodontal bone loss during OTM, however, have not yet been investigated.

Material and methods

40 male Fischer344 rats were divided into four groups: 1.5 ml tap water/day p.o. (control, 1), additional 7.8 mg/kg/day etoricoxib (normal dose) for three (2) or seven (3) days/week and 13.1 mg/kg/day (high dose) for seven days/week, respectively (4). After a week of premedication, OTM in anterior direction of the first left upper molar was performed for 28 days by means of a nickel-titanium coil spring (0.25 N). We quantified OTM-associated dental root resorptions, osteoclastogenesis, trabecular number and periodontal bone loss by histomorphometrical, histochemical and μCT analyses of the disected tooth-bearing upper jaw sections.

Results

After 28 days of OTM, associated reduction of trabecular number seemed to be slightly alleviated by high doses of etoricoxib, whereas no significant other etoricoxib effects in the doses administered could be detected regarding OTM-induced or -associated dental root resorptions, osteoclastogenesis or periodontal bone loss.

Conclusions

Dental root resorptions, osteoclastogenesis and periodontal bone loss during OTM in rats were not significantly affected by etoricoxib in the clinically relevant dosages investigated with only a slight inhibitory effect on bone remodelling to be expected at high dosages. Etoricoxib is therefore not suitable for the prevention of these detrimental effects, but could be a suitable analgesic during OTM, as it has been reported not to affect tooth movement.

Introduction

Orthodontic correction of malpositioned teeth is of medical importance, as malocclusions are assumed to be associated with an increased risk of caries and periodontitis (Alsulaiman et al., 2018, Sá-Pinto et al., 2018). Both diseases have a high prevalence and can cause reduced chewing function, toothache and at worst a total loss of teeth. Furthermore, malpositioned teeth represent a distinct psychological burden for patients (Dimberg et al., 2015). Therefore orthodontics has an important prophylactic function for the development and progression of these diseases. To achieve orthodontic tooth movement (OTM) for the correction of tooth position, mechanical forces are applied to misaligned teeth. This creates pressure and tension zones within the periodontal ligament, a connective tissue adjoining the tooth to the surrounding alveolar bone, leading to a sterile pseudo-inflammatory reaction, which is characterized by an increased expression of proinflammatory cytokines, angiogenesis, pain and bone remodelling (Meikle, 2006, Wolf et al., 2016b), mediated by periodontal ligament fibroblasts, osteocytes and cells of the immune system such as T cells (Wolf et al., 2016a, Kirschneck et al., 2019, Tresguerres et al., 2020). Thereby, osteoclastogenesis and bone resorption are induced primarily in compression areas, whereas osteoblastogenesis and bone formation occur primarily in the tension areas of the periodontal ligament (Meikle, 2006).

Many patients regularly use non-steroidal anti-inflammatory drugs (NSAIDs) as painkillers without a prescription (Turpin, 2009). These pharmacologically active substances have the potential to modulate OTM on a cellular-molecular level and may impact on dental root resorption or periodontal bone loss (Bartzela et al., 2009). A common feature of NSAIDs is the inhibition of the enzyme cyclooxygenase (COX) (Karthi et al., 2012), which catalyzes the synthesis of prostaglandins from arachidonic acid (Katzung, 2018). Especially the proinflammatory prostaglandin E2 plays an essential role in tooth movement (Meikle, 2006). Cyclooxygenase exists in at least two isoforms COX-1 and COX-2 with COX-2 being primarily expressed during inflammation, whereas COX-1 regulates physiological functions and is constitutively expressed (Kirschneck et al., 2017, Kirschneck et al., 2018). Numerous studies demonstrated that the administration of nonspecific NSAID reduced OTM in animals (Howell et al., 1991, Wong et al., 1992, Giunta et al., 1995, Arias and Marquez-Orozco, 2006, Gonzales et al., 2009, Knop et al., 2012) and in humans (Jeffcoat et al., 1988, Sari et al., 2004, Jeffcoat et al., 1995). These NSAID are therefore not recommended during orthodontic therapy (Walker and Buring, 2001). Due to the side effects of these non-specific COX inhibitors such as an increased risk for gastric ulcera, a new class of NSAID called coxibs was developed specifically inhibiting the isoform COX-2. Of these, the NSAID etoricoxib has the highest available COX-2 selectivity of 1:344 (COX1:2) (Patrignani et al., 2003, Tacconelli et al., 2004, Martina et al., 2005). It is the only coxib currently approved in the dental field for the treatment of postoperative toothache and for analgesic use, thus it is of particular interest in dentistry.

Recently it has been shown radiologically in a rat model that at clinically relevant doses, etoricoxib seems to have only a marginal effect on cranial growth and OTM (Kirschneck et al., 2018), whereas its analgestic efficacy for the treatment of orthodontic pain is excellent, as shown in a clinical RCT study (Gupta et al., 2014). Etoricoxib furthermore did not alter periodontal-ligament-fibroblast-mediated inflammation, extracellular matrix remodelling or osteoclastogenesis during simulated orthodontic compressive strain in vitro (Kirschneck et al., 2019). In these studies, however, no histological or tissue analyses have been performed, corroborating the observed effects of etoricoxib on cranial growth and OTM at the tissue level. Furthermore, the effects of etoricoxib, administered at clinically relevant doses during OTM, on undesired dental root resorptions, osteoclastogenesis, trabecular number in the alveolar bone and periodontal bone loss have not yet been studied so far.

Section snippets

Experimental animals and housing

After an acclimatization period of one week after shipment, 40 male 7-weeks-old Fischer-344 rats (F344/DuCrl, CDF®, Sulzfeld, Germany, mean gross body weight of 202 ± 10 g) were included in the experimental setup. The animals were housed in type IV metal grid polycarbonate cages (Makrolon®) filled with germ-reduced fibre softwood shavings (type ¾, Altromin, Soest, Germany) in a conventional animal laboratory (room temperature of 21 ± 1 °C, 25 Pa overpressure, 16 air changes per hour, 55 ± 10% humidity,

Effects of etoricoxib on trabecular number during OTM

Trabecular number (TbN) tended to be reduced by 28 days of OTM both in the non-medicated group (p = 0.0849) and the animals receiving normal dose etoricoxib for three days per week (p = 0.0609), whereas during normal dose etoricoxib medication for seven days (p = 0.2449) and high dose etoricoxib medication (p = 0.5786) this diminishing effect of OTM on trabecular number was not present.

Effects of etoricoxib on periodontal bone loss during OTM

Periodontal bone loss was significantly increased after 28 days of OTM at the orthodontically treated jaw side

Discussion

The aim of this study was to investigate the impact of different clinically relevant dosage protocols of the highly COX-2 selective NSAID and painkiller etoricoxib on osteoclastogenesis, trabecular number in alveolar bone, undesired dental root resorptions and periodontal bone loss during orthodontic tooth movement (OTM), which in conjunction with cranial growth has been reported before to be only marginally affected by etoricoxib medication and this only at high dosages (Kirschneck et al., 2018

Conclusions

Our results in an animal model indicate that a medication with etoricoxib in clinically relevant doses does not affect osteoclastogenesis, trabecular number in the aleveolar bone and remodelling, dental root resorptions or periodontal bone loss to a clinically relevant extent. Together with the finding that also orthodontic tooth movement itself is only marginally inhibited and only by high etoricoxib doses, etoricoxib might be a clinically valid alternative to the current standard analgesic in

Declaration of interests

None.

Author contributions

CK: conceptualization, writing, methodology, performing animal experiments, supervision. FW: μCT analysis, staining, visualization. FC: reviewing, editing. MBL: reviewing, editing. PP: supervision, reviewing, editing. AS: writing, data curation, performing animal experiments, supervision.

Ethical statement

The work was performed and reported in accordance with the corresponding national authorities (approval ID 55.2 DMS-2532-2-276, Government of Lower Franconia, Bavaria, Germany), the German Animal Welfare Act and EU Directive 2010/63/EU for animal experiments as well as the Uniform Standards for manuscripts submitted to biomedical journals (ICMJE) and the official NC3Rs ARRIVE guidelines for the Reporting of In Vivo Experiments in Animal Research.

Acknowledgments

The authors thank Mrs. Kathrin Bauer and Mrs. Eva Zaglauer for their support during the animal experiments and histological stainings and Dr. Birgit Striegl for performing the μCT analysis (DFG-Nr.: INST 102/11-1 FUGG). CK received funding from the German Orthodontic Society DGKFO (Kirschneck 01/12/2015).

References (44)

  • E. Sari et al.

    Comparison of some effects of acetylsalicylic acid and rofecoxib during orthodontic tooth movement

    Am. J. Orthod. Dentofacial Orthop.

    (2004)
  • F.G.F. Tresguerres et al.

    The osteocyte: a multifunctional cell within the bone

    Ann. Anat.

    (2020)
  • D.L. Turpin

    Medications weigh-in on tooth movement

    Am. J. Orthod. Dentofacial Orthop.

    (2009)
  • A. Wong et al.

    The effect of acetylsalicylic acid on orthodontic tooth movement in the guinea pig

    Am. J. Orthod. Dentofacial Orthop.

    (1992)
  • N.G.B. Agrawal et al.

    Single- and multiple-dose pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, in man

    J. Clin. Pharmacol.

    (2003)
  • N. Brezniak et al.

    Orthodontic root resorption: a new perspective

    Angle Orthod.

    (2016)
  • L. Dimberg et al.

    The impact of malocclusion on the quality of life among children and adolescents: a systematic review of quantitative studies

    Eur. J. Orthod.

    (2015)
  • G. Gomori

    Histochemical methods for acid phosphatase

    J. Histochem. Cytochem.

    (1956)
  • C. Gonzales et al.

    Effects of steroidal and nonsteroidal drugs on tooth movement and root resorption in the rat molar

    Angle Orthod.

    (2009)
  • M. Gupta et al.

    Controlling pain during orthodontic fixed appliance therapy with non-steroidal anti-inflammatory drugs (NSAID): a randomized, double-blinded, placebo-controlled study

    J. Orofac. Orthop.

    (2014)
  • T.H. Howell et al.

    Inhibition of alveolar bone loss in beagles with the NSAID naproxen

    J. Periodont. Res.

    (1991)
  • M.K. Jeffcoat et al.

    A comparison of topical ketorolac, systemic flurbiprofen, and placebo for the inhibition of bone loss in adult periodontitis

    J. Periodontol.

    (1995)
  • Cited by (0)

    View full text