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The effect of indomethacin (an aspirin-like drug) on the rate of orthodontic tooth movement
The effect of indomethacin (an aspirin-like drug) on the rate of orthodontic tooth movement A. Brent Chumbley and Orhan C. Tuncay
Lexington, Ky. Prostaglandins (PGs) have been suggested as mediators of bone resorption. In addition, their presence in the periodontal tissues has also been demonstrated. To characterize the involvement of PGs in orthodontic tooth movement, indomethacin, an aspirin-like drug and a potent inhibitor of PG synthesis, was administered orally to six mongrel cats; another group of six animals served as controls. These animals were fitted with orthodontic appliances that consisted of coil springs stretching between the right side maxillary and mandibular canines and third premolars. The data for toothmovement measurements were analyzed by repeated measures factorial analysis of variance. At the end of the 21-day experimental period, the rate of tooth movement in experimental animals was approximately one half of controls (P < 0.01). Findings of this study imply a significant role for PGs in bone resorption during orthodontic therapy. It is recommended that aspirin-like drugs not be administered to patients undergoing orthodontic tooth movement as it may extend the treatment time. (AM J ORTHOD 89: 312-314, 1986.)
Key words: Prostaglandins, indomethacin, orthodontic tooth movement
Movement of teeth during orthodontic treatment is dependent upon resorption of the alveolar bone. Although the histology of this remodeling process has been studied extensively, the biochemical mediators that inltiate or facilitate it are still not fully understood. In recent years certain intracellular compounds, most notably the cyclic nucleotides and prostaglandins (PGs), have been suggested as mediators of alveolar bone resorption. 1,2 Unfortunately, although cyclic AMP may well play an important role in bone remodeling, its level within the periodontium does not seem to be correlated with the rate of orthodontic tooth movement.3 PGs, however, may play a more direct role; they cause bone resorption in vitro4 and they are present in the periodontal tissues of teeth that have been moved orthodontically, s Accordingly, if PGs are involved in bone resorption during orthodontic treatment, blocking the synthesis of these compounds should result in slower tooth movement. The present study was designed to test this hypothesis.
MATERIALS AND METHODS
Twelve mongrel cats, 12 to 18 months old and weighing 5 kg, were divided randomly into two groups of six. The experimental group received 5 mg/kg/day oral indomethacin (Indocin*); the control animals received placebo tablets of cat chow. All animals were anesthetized with 15 mg/kg of ketamine (Ketalart) and circumferential grooves cut around the maxillary and mandibular right canines and third premolars. Closed coil springs (Fig. 1) delivering 250 g were then stretched between these teeth and tied to the grooves in such a way as to avoid trauma from the occlusion? Finally, reference bur holes were placed near the gingival margins of the affected teeth and used as positive landmarks from which to measure tooth movement. The distances between the canine third-premolar bur holes and between cusp tips were measured with calipers to the nearest hundredth of millimeter immediately after insertion of the appliances and again at 21 days. The data were. analyzed by 2 x 2 repeated measures factorial analysis of variance. 7'8 RESULTS
From the Department of Orthodontics, University of Kentucky, College of Dentistry. This article is based on the thesis for partial fulfillment of the requirements for a Master of Science in Dentistry degree, University of Kentucky, Graduate School, 1980.
312
The animals tolerated the experimental procedures well and the application of orthodontic forces resulted *Merck Sharp & Dohme, West Point, Pa. ~'Parke-Davis, Morris Plains, N.J.
Volume89 Number4
Effect of indomethacin on rate of orthodontic tooth movement 313
Fig. 1. Coil springs stretching between third premolars and canines. Table I. Mean tooth movement measurements at the cusp tips and reference holes (N = 6 per cell)
Indomethacin
Table II. Repeated measures factorial design ANOVA for tooth movement measurements (2 x 2)
Control
I
Arch
Tip
Hole
Tip
Hole
Maxilla Mandible Overall
1.70 1.26 1.48
0.92 0.63 0.77
3.42 2.69 3.06
1.98 1.19 1.58
Source of variation
DISCUSSION
The findings of this study suggest that prostaglandins may play an important role in bone resorption during orthodontic tooth movement. The effect of indomethacin on bone resorption is primarily mediated bythe inhibition of the prostaglandin synthetase enzyme system, although this drug can also inhibit prostaglandin 15' dehydrogenase, collagenase, and phosphodiesterase.9 The plasma concentrations required for such
Tip
I
Hole
Among cats Indomethacin
10.84 * *
7.56 *
7.96* 0.61
17.79"* 3.58
Within cats Arch Indomethacin × arch
in significant tooth movement. In general, the experimental animals showed significantly less tooth movement than did the control group; the average amount of space closure was greater in the maxilla regardless of group (Tables I and II). As would be expected, the measurements taken between cusp tips showed a greater change (P < 0.01) than did the measurements taken between bur holes (P < 0.05). For both measurements, however, the control cats exhibited approximately twice as much tooth movement than did the experimental animals.
F Ratio
*P < 0.05. **P < 0.01.
inhibitions, however, are substantially higher than the levels required for PG synthetase inhibition and are 10 to 100 times greater than the levels used in this study. Accordingly, the results of the present study are probably caused by the inhibition of PG synthetase and not other systems. Animals in this study, although exhibiting slight weight loss, did not experience any overt gastrointestinal side effects of the drug administered. Prostaglandins have also been implicated in the resorption of bone in inflammatory periodontal disease, lo Interestingly, patients suffering from chronic arthritis who take aspirin persistently exhibit less periodontal bone loss than the age-matched general population, even if they are unable to maintain a good oral hygiene regimen.11 Indeed, it has been our clinical experience and that of other practitioners in the region that patients taking aspirin or aspirin-like drugs show very slow tooth
314
Chumbley and Tuncay
m o v e m e n t and w h e n they are taken off these antiinflammatory medications, the difference is striking. It is possible that bone resorption during orthodontic tooth m o v e m e n t has the same c e l l u l a r m e c h a n i s m s as those of inflammatory periodontal disease. If this is so, PGs would be expected to play an important role in both processes. It has been shown that PGs have an effect during the earlier stages o f periodontal tissue response to tooth movement.~2 Certainly this study cannot implicate PGs as the sole agent responsible for b o n e resorption. Their production, however, m a y be an intermediary step in the chain o f events b e t w e e n mechanical force application and the removal of calcified tissue. ~3 According to K i n g and T h i e m s , 14'~5 the bone resorbing factor is a heatstable, n o n d i a l y z a b l e large molecule and it m a y be conjectured that prostaglandins are instrumental in its production. Attempts were m a d e to measure the distance between the canines and the adjacent incisors; however, as the canines m o v e d distally, the incisors developed sufficient mobility to preclude the reliable positioning of the calipers. Indeed this d i m e n s i o n occasionally appeared to d e c r e a s e - - a n o u t c o m e that is clearly contrary to reason and one that casts doubt on the m e a s u r e m e n t of c a n i n e m o v e m e n t relative to the incisors. 16 In summary, administration of indomethacin, an aspirin-like drug, slows the rate of tooth m o v e m e n t - - a n effect that is probably mediated through the inhibition of P G synthesis. The authors are indebted to Dr. Lysle E. Johnston, Jr. for his help wit h the preparation of this manuscript. This study was supported by a grant from University of Kentucky Research Foundation and by the University of Kentucky Orthodontic Alumni. REFERENCES 1. Davidovitch Z, Montgomery PC, Eckerdal O, Gustafson GT, et al: Cellular localization of cyclic AMP in periodontal tissues during experimenta! tooth movement in cats. Calcif Tissue Res 19: 317-329, 1976.
Am. J. Orthod. April 1986
2. Yamasaki K: The role of cyclic AMP, calcium and prostaglandins in the induction of osteoclastic bone resorption associated with experimental tooth movement. J Dent Res 62: 877-881, 1983. 3. Burrow SJ: Effects of diazepam induced cyclic AMP on orthodontic tooth movement in cats. Master's thesis, University of Kentucky, 1978. 4. Klein DC, Raisz LG: Stimulation of bone resorption in tissue culture. Endocrinology 86: 1436-1440, 1971. 5. Shanfeld JL, Davidovitch Z: Extraction and simultaneous measurement of cyclic AMP and prostaglandin E2 from bone. J Dent Res 59(Abstract): Special Issue A, 1980. 6. Davidovitch Z, Shanfeld JL: Cyclic AMP levels in alveolar bone of 0rthodontically treated cats. Arch Oral Biol 20: 567-574, 1975. 7. Winer B]: Statistical principles in experimental design. New York, 1962, McGraw-Hill, pp 349-351. 8. Steel RGD, Torrie JH: Principles and procedures of statistics with special reference to biological sciences, New York, 1960, McGraw-Hill, p 344. 9. Flower 1LhDrugs which inhibit prostaglandin biosynthesis. Pharmacol Rev 26: 1-4, 1979. 10. Goodson JM, Dewhirst FE, Brunetti A: Prostaglandin E2 levels in human periodontal disease. Prostaglandins 6: 81-85, 1974. 11. Feldman RS, House JE, Chauncey HH, Goldhaber P: Inhibition of alveolar bone loss in humans by aspirin. J Dent Res 59(Abstract): Special Issue A, 1980. 12. Syssens JP: A study of the influence of 16, 16 dimethyl PGE2 in experimental tooth movement. MSD thesis, St. Louis University, 1981. 13. Mostafa YA, Weaks-Dybvig M, Osdo!~yP: Orchestration of tooth movement. AM J ORTHOD83" 245-250, 1983. 14. King GJ, Thiems S: Chemical mediation of bone resorption induced by tooth movement in the rat. Arch Oral Biol 24:811815, 1979. 15. King GJ, Fischlschwiger W: The effect of force magnitude on extractable bone resorptive activity and cemental cratering in orthodontic tooth movement. J Dent Res 61: 775-779, 1982. 16. Davidovitch Z, Finkelson M, Steigman S, et al: Electric currents, bone remodeling and orthodontic tooth movement. Parts I and II. AM J ORTHOD77: 14-47, 1980. Reprint requests to:
Dr. Orhan C. Tuncay Department of Orthodontics University of Kentucky College of Dentistry Lexington, KY 40536-0084
Lexington, Ky. Prostaglandins (PGs) have been suggested as mediators of bone resorption. In addition, their presence in the periodontal tissues has also been demonstrated. To characterize the involvement of PGs in orthodontic tooth movement, indomethacin, an aspirin-like drug and a potent inhibitor of PG synthesis, was administered orally to six mongrel cats; another group of six animals served as controls. These animals were fitted with orthodontic appliances that consisted of coil springs stretching between the right side maxillary and mandibular canines and third premolars. The data for toothmovement measurements were analyzed by repeated measures factorial analysis of variance. At the end of the 21-day experimental period, the rate of tooth movement in experimental animals was approximately one half of controls (P < 0.01). Findings of this study imply a significant role for PGs in bone resorption during orthodontic therapy. It is recommended that aspirin-like drugs not be administered to patients undergoing orthodontic tooth movement as it may extend the treatment time. (AM J ORTHOD 89: 312-314, 1986.)
Key words: Prostaglandins, indomethacin, orthodontic tooth movement
Movement of teeth during orthodontic treatment is dependent upon resorption of the alveolar bone. Although the histology of this remodeling process has been studied extensively, the biochemical mediators that inltiate or facilitate it are still not fully understood. In recent years certain intracellular compounds, most notably the cyclic nucleotides and prostaglandins (PGs), have been suggested as mediators of alveolar bone resorption. 1,2 Unfortunately, although cyclic AMP may well play an important role in bone remodeling, its level within the periodontium does not seem to be correlated with the rate of orthodontic tooth movement.3 PGs, however, may play a more direct role; they cause bone resorption in vitro4 and they are present in the periodontal tissues of teeth that have been moved orthodontically, s Accordingly, if PGs are involved in bone resorption during orthodontic treatment, blocking the synthesis of these compounds should result in slower tooth movement. The present study was designed to test this hypothesis.
MATERIALS AND METHODS
Twelve mongrel cats, 12 to 18 months old and weighing 5 kg, were divided randomly into two groups of six. The experimental group received 5 mg/kg/day oral indomethacin (Indocin*); the control animals received placebo tablets of cat chow. All animals were anesthetized with 15 mg/kg of ketamine (Ketalart) and circumferential grooves cut around the maxillary and mandibular right canines and third premolars. Closed coil springs (Fig. 1) delivering 250 g were then stretched between these teeth and tied to the grooves in such a way as to avoid trauma from the occlusion? Finally, reference bur holes were placed near the gingival margins of the affected teeth and used as positive landmarks from which to measure tooth movement. The distances between the canine third-premolar bur holes and between cusp tips were measured with calipers to the nearest hundredth of millimeter immediately after insertion of the appliances and again at 21 days. The data were. analyzed by 2 x 2 repeated measures factorial analysis of variance. 7'8 RESULTS
From the Department of Orthodontics, University of Kentucky, College of Dentistry. This article is based on the thesis for partial fulfillment of the requirements for a Master of Science in Dentistry degree, University of Kentucky, Graduate School, 1980.
312
The animals tolerated the experimental procedures well and the application of orthodontic forces resulted *Merck Sharp & Dohme, West Point, Pa. ~'Parke-Davis, Morris Plains, N.J.
Volume89 Number4
Effect of indomethacin on rate of orthodontic tooth movement 313
Fig. 1. Coil springs stretching between third premolars and canines. Table I. Mean tooth movement measurements at the cusp tips and reference holes (N = 6 per cell)
Indomethacin
Table II. Repeated measures factorial design ANOVA for tooth movement measurements (2 x 2)
Control
I
Arch
Tip
Hole
Tip
Hole
Maxilla Mandible Overall
1.70 1.26 1.48
0.92 0.63 0.77
3.42 2.69 3.06
1.98 1.19 1.58
Source of variation
DISCUSSION
The findings of this study suggest that prostaglandins may play an important role in bone resorption during orthodontic tooth movement. The effect of indomethacin on bone resorption is primarily mediated bythe inhibition of the prostaglandin synthetase enzyme system, although this drug can also inhibit prostaglandin 15' dehydrogenase, collagenase, and phosphodiesterase.9 The plasma concentrations required for such
Tip
I
Hole
Among cats Indomethacin
10.84 * *
7.56 *
7.96* 0.61
17.79"* 3.58
Within cats Arch Indomethacin × arch
in significant tooth movement. In general, the experimental animals showed significantly less tooth movement than did the control group; the average amount of space closure was greater in the maxilla regardless of group (Tables I and II). As would be expected, the measurements taken between cusp tips showed a greater change (P < 0.01) than did the measurements taken between bur holes (P < 0.05). For both measurements, however, the control cats exhibited approximately twice as much tooth movement than did the experimental animals.
F Ratio
*P < 0.05. **P < 0.01.
inhibitions, however, are substantially higher than the levels required for PG synthetase inhibition and are 10 to 100 times greater than the levels used in this study. Accordingly, the results of the present study are probably caused by the inhibition of PG synthetase and not other systems. Animals in this study, although exhibiting slight weight loss, did not experience any overt gastrointestinal side effects of the drug administered. Prostaglandins have also been implicated in the resorption of bone in inflammatory periodontal disease, lo Interestingly, patients suffering from chronic arthritis who take aspirin persistently exhibit less periodontal bone loss than the age-matched general population, even if they are unable to maintain a good oral hygiene regimen.11 Indeed, it has been our clinical experience and that of other practitioners in the region that patients taking aspirin or aspirin-like drugs show very slow tooth
314
Chumbley and Tuncay
m o v e m e n t and w h e n they are taken off these antiinflammatory medications, the difference is striking. It is possible that bone resorption during orthodontic tooth m o v e m e n t has the same c e l l u l a r m e c h a n i s m s as those of inflammatory periodontal disease. If this is so, PGs would be expected to play an important role in both processes. It has been shown that PGs have an effect during the earlier stages o f periodontal tissue response to tooth movement.~2 Certainly this study cannot implicate PGs as the sole agent responsible for b o n e resorption. Their production, however, m a y be an intermediary step in the chain o f events b e t w e e n mechanical force application and the removal of calcified tissue. ~3 According to K i n g and T h i e m s , 14'~5 the bone resorbing factor is a heatstable, n o n d i a l y z a b l e large molecule and it m a y be conjectured that prostaglandins are instrumental in its production. Attempts were m a d e to measure the distance between the canines and the adjacent incisors; however, as the canines m o v e d distally, the incisors developed sufficient mobility to preclude the reliable positioning of the calipers. Indeed this d i m e n s i o n occasionally appeared to d e c r e a s e - - a n o u t c o m e that is clearly contrary to reason and one that casts doubt on the m e a s u r e m e n t of c a n i n e m o v e m e n t relative to the incisors. 16 In summary, administration of indomethacin, an aspirin-like drug, slows the rate of tooth m o v e m e n t - - a n effect that is probably mediated through the inhibition of P G synthesis. The authors are indebted to Dr. Lysle E. Johnston, Jr. for his help wit h the preparation of this manuscript. This study was supported by a grant from University of Kentucky Research Foundation and by the University of Kentucky Orthodontic Alumni. REFERENCES 1. Davidovitch Z, Montgomery PC, Eckerdal O, Gustafson GT, et al: Cellular localization of cyclic AMP in periodontal tissues during experimenta! tooth movement in cats. Calcif Tissue Res 19: 317-329, 1976.
Am. J. Orthod. April 1986
2. Yamasaki K: The role of cyclic AMP, calcium and prostaglandins in the induction of osteoclastic bone resorption associated with experimental tooth movement. J Dent Res 62: 877-881, 1983. 3. Burrow SJ: Effects of diazepam induced cyclic AMP on orthodontic tooth movement in cats. Master's thesis, University of Kentucky, 1978. 4. Klein DC, Raisz LG: Stimulation of bone resorption in tissue culture. Endocrinology 86: 1436-1440, 1971. 5. Shanfeld JL, Davidovitch Z: Extraction and simultaneous measurement of cyclic AMP and prostaglandin E2 from bone. J Dent Res 59(Abstract): Special Issue A, 1980. 6. Davidovitch Z, Shanfeld JL: Cyclic AMP levels in alveolar bone of 0rthodontically treated cats. Arch Oral Biol 20: 567-574, 1975. 7. Winer B]: Statistical principles in experimental design. New York, 1962, McGraw-Hill, pp 349-351. 8. Steel RGD, Torrie JH: Principles and procedures of statistics with special reference to biological sciences, New York, 1960, McGraw-Hill, p 344. 9. Flower 1LhDrugs which inhibit prostaglandin biosynthesis. Pharmacol Rev 26: 1-4, 1979. 10. Goodson JM, Dewhirst FE, Brunetti A: Prostaglandin E2 levels in human periodontal disease. Prostaglandins 6: 81-85, 1974. 11. Feldman RS, House JE, Chauncey HH, Goldhaber P: Inhibition of alveolar bone loss in humans by aspirin. J Dent Res 59(Abstract): Special Issue A, 1980. 12. Syssens JP: A study of the influence of 16, 16 dimethyl PGE2 in experimental tooth movement. MSD thesis, St. Louis University, 1981. 13. Mostafa YA, Weaks-Dybvig M, Osdo!~yP: Orchestration of tooth movement. AM J ORTHOD83" 245-250, 1983. 14. King GJ, Thiems S: Chemical mediation of bone resorption induced by tooth movement in the rat. Arch Oral Biol 24:811815, 1979. 15. King GJ, Fischlschwiger W: The effect of force magnitude on extractable bone resorptive activity and cemental cratering in orthodontic tooth movement. J Dent Res 61: 775-779, 1982. 16. Davidovitch Z, Finkelson M, Steigman S, et al: Electric currents, bone remodeling and orthodontic tooth movement. Parts I and II. AM J ORTHOD77: 14-47, 1980. Reprint requests to:
Dr. Orhan C. Tuncay Department of Orthodontics University of Kentucky College of Dentistry Lexington, KY 40536-0084