Low-dose doxycycline inhibits bone resorption associated with apical periodontitis

Low-dose doxycycline inhibits bone resorptionassociated with apical periodontitis Z. Metzger1,2, D. Belkin1, N. Kariv3, M. Dotan1 & A. Kfir21Department of Oral Biology and 2Department of Endodontology, The Maurice and Gabriela Goldschleger School of DentalMedicine, 3Glasberg Tower for Medical Research, Tel Aviv University, Tel Aviv, Israel was determined and used to compare the groups.
Statistical analysis was completed using anova with Metzger Z, Belkin D, Kariv N, Dotan M, Kfir A. Low-dose doxycycline inhibits bone resorption associated with apical Results The mean doxycycline serum level in group periodontitis. International Endodontic Journal, 41, 303–309, A was 0.22(±0.03) lg mL)1 and in group B below the detection level of the assay (<0.062 lg mL)1). The Aim To test the effect of low-dose doxycycline on bone mean area of the periapical bone resorption in the resorption associated with apical periodontitis.
control group C was 2.91(±0.61) mm2. In animals Methodology Apical periodontitis was induced by treated with a low-dose doxycycline, the mean size of occlusal pulp exposure in the mandibular first molars of the bone resorption was significantly smaller at 36 rats. Animals were divided into three groups of 12: 1.59(±0.59) mm2 (group A) and 1.72(±0.85) mm2 group A received doxycycline in drinking water at a (group B) (P ¼ 0.001). No significant difference was dose of 5.85 mg day)1; group B received a dose of found in the area of the bone resorption between these 1.48 mg day)1 (one-quarter of the original dose); and group C received no medicament and served as the control. A bioassay determined the doxycycline serum area of bone resorption associated with apical peri- levels. After 21 days, the mandibles were removed, odontitis in the mandibular first molar teeth of rats.
radiographed and the radiographs scanned to generate Keywords: apical periodontitis, bone resorption, digital images. These images were analysed morpho- metrically and the total area of the periapical boneresorption of the mesial and distal roots of each tooth Received 1 March 2007; accepted 12 October 2007 b, derived from these cells, trigger periapical bone resorption (Wang & Stashenko 1993).
Apical periodontitis develops in response to bacterial Periapical bone resorption may be considered a mere colonization of the root canal. Host response against undesirable side effect of the essential and successful bacteria emerging through the apical foramen success- protective host response at this site of potential bacte- fully prevents their spread to other sites. Activated rial penetration (Metzger 2000). However, it is the macrophages and activated T-lymphocytes serve as major clinical hallmark of apical periodontitis. The essential components of this response. Nevertheless, presence of bone resorption indicates disease whilst locally produced inflammatory cytokines, such as IL1b healing is monitored by its reversal and by reduction ofthe periapical radiolucency. Persistence of the lesionindicates that the balance between bone resorption andhealing is still in favour of the former.
Correspondence: Z. Metzger, School of Dental Medicine, Tel For several decades, the main, if not only, interven- Aviv University, Ramat Aviv, Tel Aviv 69978, Israel(Tel.: +972547956125; fax: +97236409250; e-mail: tion in apical periodontitis consisted of effective International Endodontic Journal, 41, 303–309, 2008 Doxycycline inhibits PA lesions Metzger et al.
bacterial elimination from the root canal. However, 2004, Preshaw et al. 2004a,b). Its effect has been recent advances in understanding the mechanisms attributed primarily to inhibition of metallo-proteases, involved in apical periodontitis allow consideration of essential for the breakdown of connective tissue and other, additional, means of intervention (Metzger bone resorption (Golub et al. 1998, Ramamurthy et al.
2000). Agents that may inhibit local bone resorption 2002). On the other hand, some reports indicate that and thus favourably shift the balance between healing tetracyclines may also be effective in reducing the and resorption, once bacteria have been eliminated, amounts of IL-1 released by activated macrophages may be considered. Enhancement of healing kinetics using a pharmacological intervention presents an The present study was designed to test the effect of attractive option. This may allow earlier decisions systemically administrated low-dose doxycycline on the regarding the survival and potential prosthodontic use bone resorption associated with induced apical peri- Three main pharmacological targets can be identified: local cytokine production, their effect on their target cells and the bone resorption process itself. Gluco-corticoids may be used to inhibit the local production of The Animal Care Committee of Tel Aviv University IL-1 by activated macrophages in the inflamed periapi- approved the experimental protocol. During the exper- cal tissues. This occurs through a post-transcriptional iment, animals were treated according to the standards mechanism (Politis et al. 1992). Recently, dexametha- set by the Committee. No signs of stress or discomfort sone was shown to inhibit the formation of bone were observed in any animal (inspected daily). Individ- resorption associated with apical periodontitis in rats ual weight-gain curves served as an additional indica- (Metzger et al. 2002). The potential of IL-1-receptor- tor of the well being of the animals.
antagonist was also tested in the same model; theinhibition of the effect of IL-1 on its target cells inhibited periapical bone resorption (Stashenko et al. 1998).
The present study was designed to test another Apical periodontitis was induced in rats by the method pharmacological agent that is known to affect the bone first described by Kakehashi et al. (1965) and allowed resorption process: doxycycline, a member of the to develop for 21 days. Systemic doxycycline was tetracycline family. Doxycycline has been widely used administered and its effect on the size of the bone both experimentally and clinically to control and resorption evaluated. The experiment included three inhibit bone resorption (Grevstad 1993, Chang et al.
groups of 12 rats each: group A received a low-dose of 1994, Grevstad & Boe 1995, Cummings & Torabinejad doxycycline in drinking water throughout the experi- 2000, Bezerra et al. 2002, Yaffe et al. 2003, Preshaw ment; group B received one-quarter of the former dose; et al. 2004a, Buduneli et al. 2005). This effect of and group C received no doxycycline and served as the tetracyclines is independent of their antimicrobial activity (Golub et al. 1998). The inhibition of boneresorption by doxycycline occurs even when a low, sub-antimicrobial dose is administered (Bezerra et al.
2002, Buduneli et al. 2005). Furthermore, chemical The study used 36 female Wistar rats (Tel Aviv University breeding) which were randomly divided into CMT-8), which lack any antibacterial effects, are still three groups of 12 animals each. At the start of the effective in the inhibition of bone resorption (Sasaki experiments, animals were 2 months old and weighed, et al. 1998, Ramamurthy et al. 2002).
on average, 229(± 14) g. Animals were kept two per At sub-antimicroboial low doses, doxycycline can be cage and fed pelleted rat diet, ad libitum. Rats were used without the risk of developing resistant bacterial weighed every third day. The weight gained in the strains (Ciancio & Ashley 1998). With no antibacterial experimental groups was compared with that of the effect, no selective pressure exists on the bacteria and control group and with normal animals (no procedure).
therefore no resistant strains emerge (Greenstein 1995, At the end of the experiment, average weight was Pallasch 2003). Low-dose doxycycline has been suc- 272(±12) g. In the experimental groups, weight gain cessfully applied to treat marginal periodontitis with did not differ from the controls or from normal animals favourable results (Ciancio & Ashley 1998, Lee et al.
International Endodontic Journal, 41, 303–309, 2008 Metzger et al. Doxycycline inhibits PA lesions Animals were anaesthetized by an intra peritonealinjection of Ketamine (90 mg kg)1; Ketaset, Barneveld,Fort Iowa, IA, USA) and Xylazine (5 mg kg)1; Kepro,the Netherlands ). The occlusal surface of each of thetwo mandibular first molars was perforated using anew No. 0.5 round bur, at low speed, exposing thepulps. The occlusal penetration was of the size of theactive part of the low speed bur used, which wasallowed to fully penetrate the pulp chamber. Penetra-tion was verified by insertion of a bent size 20 K-filethrough the occlusal opening and into the entrance of the distal root canal. The pulps remained exposed for21 days, as previously determined (Metzger et al.
Doxycycline (doxycycline hyclate; Sigma, St. Louis, MO,USA) was diluted in distilled water at a concentration ofeither 40 or 10 mg mL)1 and kept frozen in aliquots of1 mL, in the dark, until used. Each aliquot was thendiluted in 200 mL of drinking water, resulting inconcentrations of 0.2 mg mL)1 (group A) and 0.05 mg Figure 1 Periapical bone resorption area in first mandibular mL)1 (group B). Aluminium foil, wrapped around the molar of rats. (a) Larger resorption in the control group; (b) small drinking water bottles, kept the medicament out of smaller resorption in animals treated with doxycycline. Apical the light. Water bottles were replaced every second day periodontitis was induced by occlusal pulp exposure, open for and the amount consumed was recorded. Doxycycline treatment started 3 days prior to pulp exposure.
using the method described by Bennet et al. (1966).
Bacillus cereus (ATCC 11778), which is highly sensitive to tetracycline, was grown overnight in Brain–Heart At day 21, animals were anaesthetized and blood Infusion broth and 200 lL of the culture, containing samples were collected by cardiac puncture. Animals 2 · 108 colony forming units, were evenly spread on were killed using CO2 and the mandibles removed and the surface of Brain–Heart Infusion agar plates. Four placed in 2% NaOH for 48 h to facilitate thorough soft full-thickness holes, 6 mm in diameter, were prepared tissue removal. Mandibles were then stored in buffered in the agar of each plate and served as wells for the 5% formalin. The jaws were radiographed using an tested samples (Bennet et al. 1966). Serum samples, EP-21 periapical dental film (Eastman Kodak, Roches- 60 lL, were placed in each well and plates incubated ter, NY, USA) with 0.32 s exposure from a distance of aerobically at 37 °C for 24 h. A standard curve was 20 cm, using a Gendex X-ray machine (Milan, Italy).
generated in a similar manner using predetermined Jaws placed on their clean buccal side allowed a uniform angulation as previously determined (Metzger either in PBS or in PBS containing 50% normal rat et al. 2002) (Fig. 1). All radiographs were developed serum (Bennet et al. 1966). Circular inhibition zones developed around wells containing doxycycline. Twoinhibition zone diameters, perpendicular to each other,were measured and the mean diameter used as an inhibition parameter. Each serum sample and each Individual serum samples collected at the end of the point of the standard curve were assayed in quadru- experiment were assayed for doxycycline concentration plicate. The mean inhibition zone diameter of each International Endodontic Journal, 41, 303–309, 2008 Doxycycline inhibits PA lesions Metzger et al.
serum sample was calculated and its individual consumed an average of 29.3(±3.5) mL day)1 (actual doxycycline concentration determined using the stan- daily dose of 5.85(±0.69) mg per animal), and in group B, the mean consumption was 29.52(±2.77) mL day)1(actual daily doxycycline dose of 1.48(±0.14) mg peranimal).
Radiographs were scanned using an HP Photosmart film scanner (Hewlett Packard, Singapore), and theirdigital images analysed using sigma scan software Doxycycline treatment resulted in a mean serum level (SPSS Science Software, San Raffael, CA, USA). The of 0.22(±0.03) lg mL)1 in group A, with a range from borders of the radiographic image of the periapical bone 0.17 to 0.30 lg mL)1, whilst in group B serum levels resorption of the mesial and distal roots of each tooth were below the lowest detection level of the bioassay were traced and their area calculated. The area of the (<0.062 lg mL)1). No Doxycycline was detected in the root tip was excluded. Tracing was performed manu- control group. No difference was found between ally, on the screen, on an enlarged image, with the standard curves generated with and without normal operator blinded as to the animal and treatment group from which the sample came. Measurements, afterseveral initial practicing sessions, were with intra- operator reproducibility of ±8%. A total of 24 teethwith 48 periapical areas of bone resorption were The areas of the periapical bone resorption were first tested for normal distribution, using the Kolmogorov–Smirnov test (spss, version 14.0). When each root wastested alone (mesial right, distal right, mesial left, distal left), distribution in each group did not differ from anova with-repeated-measures was used to analyse the normal distribution (P ¼ 0.637, 0.990, 0.290 and weight gain of the animals. The areas of bone resorption 0.272, respectively). Nevertheless, when the total area were first tested for normal distribution, using the of both mesial and distal bone resorption of a given Kolmogorov–Smirnov test (spss, version 14.0). Once tooth was used as the parameter, distribution was this was verified (see Results), anova with-repeated- closer to normal (P ¼ 0.945 and 0.661 for left measures with Tukey’s post hoc test was used to analyse mesial + distal roots and right mesial + distal roots, the size of periapical bone resorption. Analysis was respectively). Results of analysis for distal roots alone or performed with within-subject-factors: area of the mesial roots alone gave similar results with the same individual periapical bone resorption on left and right conclusions (data not presented) Therefore, the total of and the total of areas of the resorption of the mesial and periapical areas per tooth was used as the parameter for distal roots of each given tooth for left and right sides and with between-subject-factor: treatment.
Effect of doxycycline on periapical bone resorption The area of periapical bone resorption that developedin 2.91(±0.61) mm2 (per tooth) (Table 1). In group A, Preliminary measurements were taken to determine the amount of drinking water consumed daily by resulted in a significant reduction in the size of normal rats, similar in age and weight. Mean con- sumption was 27.8(±2.6) mL day)1. On this basis, the 1.59(±0.59) mm2 (P ¼ 0.001). The lower dose of doxycycline concentration in the drinking water of doxycycline in group B (1.48(±0.14) mg day)1) also group A was set at 0.2 mg mL)1 (calculated daily dose resulted in a significant reduction in the size of of 5.4 mg per animal), and of group B at 0.05 mg mL)1 (calculated daily dose of 1.35 mg per animal).
1.72(±0.85) mm2 (P ¼ 0.001). No significant differ- The actual drinking water consumption was moni- ence in the size of bone resorption was found between tored during the experiment. In group A, animals International Endodontic Journal, 41, 303–309, 2008 Metzger et al. Doxycycline inhibits PA lesions Table 1 Effect of low-dose doxycycline on the size of periapical The present results agree with Chang et al. (1994) alveolar bone loss could also be inhibited by admin-istering 5 mg day)1 of doxycycline, a dose similar to that used in this study. Similar results with low-dose doxycycline in rats have also been reported using either nylon thread ligature (Bezerra et al. 2002) or endotoxin (Buduneli et al. 2005) to induce alveolar aMean total area of the periapical bone resorption area of the mesial and distal roots, as measured from a digitized radio- It is well documented that doxycycline inhibits periodontal bone resorption in rats. Grevstad et al.
demonstrated that surgically induced alveolar bone loss was prevented by doxycycline administered systemi- This preliminary feasibility study tested for the potential cally (Grevstad 1993, Grevstad & Boe 1995). Similar of doxycycline to modulate periapical bone resorption.
results have been reported on inhibition of surgery- The total area of periapical bone resorption surround- associated crestal bone loss by doxycycline, adminis- ing the mesial and distal roots was used to give a ‘tooth’ tered either locally (Yaffe et al. 2003) or systemically value. This was performed as this parameter had a more normal distribution than the area of either the The results of the present study are in apparent distal or mesial roots alone. As this differs from other conflict with those reported recently by Tja¨derhane studies carried out with a similar model (Stashenko et al. (2007). That study addressed a similar issue, et al. 1998, Tja¨derhane et al. 2007), statistical analysis using the same model and tested the effect of system- was also carried out on the distal and mesial bone ically administered chemically modified tetracycline resorption areas alone, with similar results.
(CMT-3), which was administered by oral gavage. This Systemic low-dose doxycycline treatment inhibited treatment was expected to inhibit periapical bone the formation of periapical bone resorption by 40–45%.
resorption by its inhibitory effect on matrix metallo- It could be possibly attributed to either its antibacterial proteinases. Their results indicate an enhancement of activity or to its inhibitory effects on bone resorption, or periapical bone resorption in animals treated with the both. Neither the higher dose (5.85 mg day)1) nor the CMT-3 rather than an inhibition, as found in the lower dose (1.48 mg day)1) resulted in serum levels present study. These results are in apparent conflict that may be considered as clinically antimicrobial in with most reports on the effect of tetracyclines or rats. A therapeutic antimicrobial doxycycline dose in CMT-3 in rats, in most of which bone resorption rats should result in serum levels ‡1 lg mL)1 (Slots & associated with marginal periodontitis was the model.
Rams 1990, Chang et al. 1994, Ramamurthy et al.
Therefore, it will be of interest to carry out a study in 2002). In the present study, the higher doxycycline which doxycycline will be compared with CMT-3, as dose resulted in a serum level of only 0.22(±0.03) lg well as to other CMT, in the same model of apical mL)1, approximately one-fifth of that of an effective therapeutic dose. Serum samples from group A partially Even with a clear effect, widespread use of tetracy- inhibited bacterial growth in the bioassay. Therefore clines has its potential drawbacks as resistant strains they could, apparently, have some antimicrobial effect may emerge through selective pressure on oral bacteria in vivo which could have contributed to the inhibited (Greenstein 1995, Pallasch 2003). Golub et al. (1998) development of the periapical bone resorption. Never- have clearly demonstrated that the effect of tetracy- theless, the lower doxycycline dose in group B resulted clines on bone resorption is independent of their in such a low serum concentration that it failed to antimicrobial properties. Furthermore, the inhibition inhibit the growth of even the extremely sensitive of matrix metallo-proteinases, essential for connective bacterium (Bacillus cereus ATCC 11778). As this dose tissue breakdown, occurs at levels well below those was as effective in inhibiting periapical bone resorption required for the antimicrobial effects (Vernillo & Rifkin as the dose that had a partial inhibitory effect in the 1998). Consequently, low, sub-antimicrobial doses of bioassay, it may indicate that the inhibitory effect of the doxycycline have been tested clinically for treatment of doxycycline was most probably through its effect on periodontal disease, with favourable results (Golub bone resorption and not its antibacterial properties.
et al. 1990, 1992, Greenstein 2004).
International Endodontic Journal, 41, 303–309, 2008 Doxycycline inhibits PA lesions Metzger et al.
The commonly used method for oral administration of doxycycline in rat studies is oral gavage, using acanula inserted into the esophagus. It has the benefit of This study was conducted at the Alpha Omega assuring an accurate dose as well as bypassing the oral Research Laboratories, as partial fulfillment of the cavity. A previous study using the same model requirements for DMD degree of D. Belkin.
concluded that dexamethasone inhibited the develop-ment of periapical bone resorption (Metzger et al.
2002). As the gavage procedure may present arecurrent stressful event for the animals, which may Bennet JV, Brito GAC, Riberio RA, Rocha FAC (1966) result in elevation of endogenous cortico-steroids, this Simplified, accurate method for antibiotic assay of clinical procedure was avoided and drinking water was used as specimens. Applied Microbiology 14, 170–7.
a substitute. This may have a drawback, as a potential Bezerra MM, Brito GA, Ribeiro RA, Rocha FA (2002) Low-dose local effect of the doxycycline cannot be precluded doxycycline prevents inflammatory bone resorption in rats.
Brazilian Journal of Medical and Biological Research 35, (Toth et al. 1986). To investigate this point a direct comparison between the two methods, using the same Buduneli E, Buduneli N, Vardar-Sengul S et al. (2005) Systemic low-dose doxycycline and alendronate administra- The present study does not preclude the possibility tion and serum interleukin-1beta, osteocalcin, and C-reac- that the doxycycline treatment affected periapical bone tive protein levels in rats. Journal of Periodontology 76, resorption also through down regulation of cytokine production. To test for this hypothesis, a study in larger Chang KM, Ramamurthy NS, McNamara TF et al. (1994) animals may be required, in which intra-canal exu- Tetracyclines inhibit Porphyromonas gingivalis-induced dates may be quantitatively tested for presence of IL 1 alveolar bone loss in rats by a non-antimicrobial mech- anism. Journal of Periodontal Research 29, 242–9.
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