Research articleImpact of NSAID etoricoxib on side effects of orthodontic 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).
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