Densitometric Evaluation Jaws and Skulls of Ovariectomized Rats Following Atorvastatin Administration: The Role of Nitric Oxide
Abstract
Statins affect the bone metabolism. Considering the role of nitric oxide (NO) in many physiological processes, this study assessed the effects of atorvastatin (ATOR) and NO on the mandible and skull bone density (BD) in ovariectomized rats. This study evaluated 48 female Sprague-Dawley rats in 6 groups (n=8). Groups 1 and 2 underwent sham surgery. Group 1 (sham) did not receive any medication, but group 2 (sham/ATOR) received atorvastatin. Groups 3 to 6 underwent ovariectomy. Group 3 (OVX) did not receive any medication, group 4 (OVX/ATOR) received atorvastatin, group 5 (OVX/L-NAME) received L-NG-nitro arginine methyl ester (L-NAME), and group 6 (OVX/ATOR/L-NAME) received both atorvastatin and L-NAME. Atorvastatin (40 mg/kg) was gavaged and L-NAME (3 mg/kg) was administered intraperitoneally for 4 weeks. All rats underwent lateral cephalometry before and after the interventions, and BD was measured at 2 points in the mandible and skull before and after the intervention by a digital densitometer. Data were analyzed by t-test, ANOVA, and Sidak test (alpha=0.05). The change in BD was 26.5±10.17 in the mandible and 22.17±9.45 in the skull in OVX group. These values were 25.63±5.55 and 28±8.59 in OVX/ATR, 1.5±7.78 and -1.88±4.39 in OVX/L-NAME, and 6.63±7.37 and 4.33±6.35 in OVX/ATOR/L-NAME, respectively. OVX/ATOR showed no significant difference (P=1), but OVX/L-NAME (P<0.001) and OVX/ATOR/L-NAME (P<0.001) groups showed significant differences with OVX group. The present findings indicated that atorvastatin had no significant effect on BD, but administration of L-NAME prevented osteoporosis in ovariectomized rats.
1. Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med 1993;94:646-50.
2. Khoury MJ. Genetic and epidemiologic approaches to the search for gene-environment interaction: the case of osteoporosis. Am J Epidemiol 1998;147:1-2.
3. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-33
4. Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation 2000;101:207-13.
5. Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature 1990;343:425-30.
6. Gazzerro P, Proto MC, Gangemi G, Malfitano AM, Ciaglia E, Pisanti S, et al. Pharmacological actions of statins: a critical appraisal in the management of cancer. Pharmacol Rev 2012;64:102-46.
7. Urist MR. Bone: formation by autoinduction. Science 1965;150:893-9.
8. Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, et al. Novel regulators of bone formation: molecular clones and activities. Science 1988;242:1528-34.
9. Fisher JE, Rogers MJ, Halasy JM, Luckman SP, Hughes DE, Masarachia PJ, et al. Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci U S A 1999;96:133-8.
10. Mundy G, Garrett R, Harris S, Chan J, Chen D, Rossini G, et al. Stimulation of bone formation in vitro and in rodents by statins. Science 1999;286:1946-9
11. Maeda T, Matsunuma A, Kawane T, Horiuchi N. Simvastatin promotes osteoblast differentiation and mineralization in MC3T3-E1 cells. Biochem Biophys Res Commun 2001;280:874-7.
12. Cicinelli E, Ignarro LJ, Lograno M, Matteo G, Falco N, Schonauer LM. Acute effects of transdermal estradiol administration on plasma levels of nitric oxide in postmenopausal women. Fertil Steril 1997;67:63-6.
13. Cicinelli E, Ignarro LJ, Schonauer LM, Matteo MG, Galantino P, Balzano G. Effects of short-term transdermal estradiol administration on plasma levels of nitric oxide in postmenopausal women. Fertil Steril 1998;69:58-61.
14. Rosselli M, Imthurn B, Keller PJ, Jackson EK, Dubey RK. Circulating nitric oxide (nitrite/nitrate) levels in postmenopausal women substituted with 17 beta-estradiol and norethisterone acetate. A two-year follow-up study. Hypertension 1995;25:848-53.
15. Stacey E, Korkia P, Hukkanen MV, Polak JM, Rutherford OM. Decreased nitric oxide levels and bone turnover in amenorrheic athletes with spinal osteopenia. J Clin Endocrinol Metab 1998;83:3056-61.
16. Lowik CW, Nibbering PH, van de Ruit M, Papapoulos SE. Inducible production of nitric oxide in osteoblast-like cells and in fetal mouse bone explants is associated with suppression of osteoclastic bone resorption. J Clin Invest 1994;93:1465-72.
17. Kasten TP, Collin-Osdoby P, Patel N, Osdoby P, Krukowski M, Misko TP, et al. Potentiation of osteoclast bone-resorption activity by inhibition of nitric oxide synthase. Proc Natl Acad Sci U S A 1994;91:3569-73.
18. MacIntyre I, Zaidi M, Alam AS, Datta HK, Moonga BS, Lidbury PS, et al. Osteoclastic inhibition: an action of nitric oxide not mediated by cyclic GMP. Proc Natl Acad Sci U S A. 1991;88:2936-40.
19. Hassanipour M, Amini-Khoei H, Shafaroodi H, Shirzadian A, Rahimi N, Imran-Khan M, et al. Atorvastatin attenuates the antinociceptive tolerance of morphine via nitric oxide dependent pathway in male mice. Brain Res Bull 2016;125:173-80.
20. Wronski TJ, Cintrón M, Dann LM. Temporal relationship between bone loss and increased bone turnover in ovariectomized rats. Calcif Tissue Int 1988;43:179-83.
21. Irie K. Three-dimensional changes of the mandible and alveolar bone in the ovariectomized rat examined by micro-focus computed tomography. 2004;46:288-93.
22. Kalu DN. The ovariectomized rat model of postmenopausal bone loss. Bone Miner 1991;15:175-91.
23. Ayukawa Y, Ogino Y, Moriyama Y, Atsuta I, Jinno Y, Kihara M, et al. Simvastatin enhances bone formation around titanium implants in rat tibiae. J Oral Rehabil 2010;37:123-30.
24. Du Z, Chen J, Yan F, Xiao Y. Effects of Simvastatin on bone healing around titanium implants in osteoporotic rats. Clin Oral Implants Res 2009;20:145-50.
25. Chuengsamarn S, Rattanamongkoulgul S, Suwanwalaikorn S, Wattanasirichaigoon S, Kaufman L. Effects of statins vs. non-statin lipid-lowering therapy on bone formation and bone mineral density biomarkers in patients with hyperlipidemia. Bone 2010;46:1011-5.
26. Gradosova I, Zivna H, Svejkovska K, Palicka V, Tichy A, Zivny P. The role of atorvastatin in bone metabolism in male albino Wistar rats. Pharmazie 2011;66:606-10.
27. Goes P, Lima AP, Melo IM, Rego RO, Lima V. Effect of Atorvastatin in radiographic density on alveolar bone loss in wistar rats. Braz Dent J 2010;21:193-8.
28. McCann R, Colleary G, Geddis C, Clarke S, Marsh D, Dickson G. P7 the effect of atorvastatin treatment on bone mineral density and fracture repair in a rat femoral fracture model. J Bone Joint Surg Br 2008;90-B:372
29. Chang B, Yang J, Li H, Lu S, Chen L, Fang P. Effects of atorvastatin on bone metabolism and bone mineral density in Wistar rats. Pharmazie 2011;66:535-7
30. Handal JA, John TK, Goldstein DT, Khurana JS, Saing M, Braitman LE, et al. Effect of atorvastatin on the cortical bones of corticosteroid treated rabbits. J Orthop Res 2012;30:872-6.
31. Braatvedt GD, Bagg W, Gamble G, Davidson J, Reid IR. The effect of atorvastatin on markers of bone turnover in patients with type 2 diabetes. Bone 2004;35:766-70.
32. Bone HG, Kiel DP, Lindsay RS, Lewiecki EM, Bolognese MA, Leary ET, et al. Effects of atorvastatin on bone in postmenopausal women with dyslipidemia: a double-blind, placebo-controlled, dose-ranging trial. J Clin Endocrinol Metab 2007;92:4671-7.
33. Wang J, Shang F, Mei Q, Wang J, Zhang R, Wang S. NO-donating genistein prodrug alleviates bone loss in ovariectomised rats. Swiss Med Wkly 2008;138:602-7.
34. Shirazi M, Nilforoushan D, Alghasi H, Dehpour AR. The role of nitric oxide in orthodontic tooth movement in rats. Angle Orthod 2002;72:211-5.
35. Hayashi K, Igarashi K, Miyoshi K, Shinoda H, Mitani H. Involvement of nitric oxide in orthodontic tooth movement in rats. Am J Orthod Dentofacial Orthop 2002;122:306-9.
36. Akin E, Gurton AU, Olmez H. Effects of nitric oxide in orthodontic tooth movement in rats. Am J Orthod Dentofacial Orthop 2004;126:608-14.
37. Talaeipour AR, Shirazi M, Kheirandish Y, Delrobaie A, Jafari F, Dehpour AR. Densitometric evaluation of skull and jaw bones after administration of thyroid hormones in rats. Dentomaxillofac Radiol 2005;34:332-6.
38. Barbosa D, de Souza RA, Xavier M, da Silva FF, Arisawa EA, Villaverde AG. Effects of low-level laser therapy (LLLT) on bone repair in rats: optical densitometry analysis. Lasers Med Sci 2013;28:651-6.
39. Horner K, Devlin H, Alsop CW, Hodgkinson IM, Adams JE. Mandibular bone mineral density as a predictor of skeletal osteoporosis. Br J Radiol 1996;69:1019-25.
2. Khoury MJ. Genetic and epidemiologic approaches to the search for gene-environment interaction: the case of osteoporosis. Am J Epidemiol 1998;147:1-2.
3. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-33
4. Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation 2000;101:207-13.
5. Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature 1990;343:425-30.
6. Gazzerro P, Proto MC, Gangemi G, Malfitano AM, Ciaglia E, Pisanti S, et al. Pharmacological actions of statins: a critical appraisal in the management of cancer. Pharmacol Rev 2012;64:102-46.
7. Urist MR. Bone: formation by autoinduction. Science 1965;150:893-9.
8. Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, et al. Novel regulators of bone formation: molecular clones and activities. Science 1988;242:1528-34.
9. Fisher JE, Rogers MJ, Halasy JM, Luckman SP, Hughes DE, Masarachia PJ, et al. Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci U S A 1999;96:133-8.
10. Mundy G, Garrett R, Harris S, Chan J, Chen D, Rossini G, et al. Stimulation of bone formation in vitro and in rodents by statins. Science 1999;286:1946-9
11. Maeda T, Matsunuma A, Kawane T, Horiuchi N. Simvastatin promotes osteoblast differentiation and mineralization in MC3T3-E1 cells. Biochem Biophys Res Commun 2001;280:874-7.
12. Cicinelli E, Ignarro LJ, Lograno M, Matteo G, Falco N, Schonauer LM. Acute effects of transdermal estradiol administration on plasma levels of nitric oxide in postmenopausal women. Fertil Steril 1997;67:63-6.
13. Cicinelli E, Ignarro LJ, Schonauer LM, Matteo MG, Galantino P, Balzano G. Effects of short-term transdermal estradiol administration on plasma levels of nitric oxide in postmenopausal women. Fertil Steril 1998;69:58-61.
14. Rosselli M, Imthurn B, Keller PJ, Jackson EK, Dubey RK. Circulating nitric oxide (nitrite/nitrate) levels in postmenopausal women substituted with 17 beta-estradiol and norethisterone acetate. A two-year follow-up study. Hypertension 1995;25:848-53.
15. Stacey E, Korkia P, Hukkanen MV, Polak JM, Rutherford OM. Decreased nitric oxide levels and bone turnover in amenorrheic athletes with spinal osteopenia. J Clin Endocrinol Metab 1998;83:3056-61.
16. Lowik CW, Nibbering PH, van de Ruit M, Papapoulos SE. Inducible production of nitric oxide in osteoblast-like cells and in fetal mouse bone explants is associated with suppression of osteoclastic bone resorption. J Clin Invest 1994;93:1465-72.
17. Kasten TP, Collin-Osdoby P, Patel N, Osdoby P, Krukowski M, Misko TP, et al. Potentiation of osteoclast bone-resorption activity by inhibition of nitric oxide synthase. Proc Natl Acad Sci U S A 1994;91:3569-73.
18. MacIntyre I, Zaidi M, Alam AS, Datta HK, Moonga BS, Lidbury PS, et al. Osteoclastic inhibition: an action of nitric oxide not mediated by cyclic GMP. Proc Natl Acad Sci U S A. 1991;88:2936-40.
19. Hassanipour M, Amini-Khoei H, Shafaroodi H, Shirzadian A, Rahimi N, Imran-Khan M, et al. Atorvastatin attenuates the antinociceptive tolerance of morphine via nitric oxide dependent pathway in male mice. Brain Res Bull 2016;125:173-80.
20. Wronski TJ, Cintrón M, Dann LM. Temporal relationship between bone loss and increased bone turnover in ovariectomized rats. Calcif Tissue Int 1988;43:179-83.
21. Irie K. Three-dimensional changes of the mandible and alveolar bone in the ovariectomized rat examined by micro-focus computed tomography. 2004;46:288-93.
22. Kalu DN. The ovariectomized rat model of postmenopausal bone loss. Bone Miner 1991;15:175-91.
23. Ayukawa Y, Ogino Y, Moriyama Y, Atsuta I, Jinno Y, Kihara M, et al. Simvastatin enhances bone formation around titanium implants in rat tibiae. J Oral Rehabil 2010;37:123-30.
24. Du Z, Chen J, Yan F, Xiao Y. Effects of Simvastatin on bone healing around titanium implants in osteoporotic rats. Clin Oral Implants Res 2009;20:145-50.
25. Chuengsamarn S, Rattanamongkoulgul S, Suwanwalaikorn S, Wattanasirichaigoon S, Kaufman L. Effects of statins vs. non-statin lipid-lowering therapy on bone formation and bone mineral density biomarkers in patients with hyperlipidemia. Bone 2010;46:1011-5.
26. Gradosova I, Zivna H, Svejkovska K, Palicka V, Tichy A, Zivny P. The role of atorvastatin in bone metabolism in male albino Wistar rats. Pharmazie 2011;66:606-10.
27. Goes P, Lima AP, Melo IM, Rego RO, Lima V. Effect of Atorvastatin in radiographic density on alveolar bone loss in wistar rats. Braz Dent J 2010;21:193-8.
28. McCann R, Colleary G, Geddis C, Clarke S, Marsh D, Dickson G. P7 the effect of atorvastatin treatment on bone mineral density and fracture repair in a rat femoral fracture model. J Bone Joint Surg Br 2008;90-B:372
29. Chang B, Yang J, Li H, Lu S, Chen L, Fang P. Effects of atorvastatin on bone metabolism and bone mineral density in Wistar rats. Pharmazie 2011;66:535-7
30. Handal JA, John TK, Goldstein DT, Khurana JS, Saing M, Braitman LE, et al. Effect of atorvastatin on the cortical bones of corticosteroid treated rabbits. J Orthop Res 2012;30:872-6.
31. Braatvedt GD, Bagg W, Gamble G, Davidson J, Reid IR. The effect of atorvastatin on markers of bone turnover in patients with type 2 diabetes. Bone 2004;35:766-70.
32. Bone HG, Kiel DP, Lindsay RS, Lewiecki EM, Bolognese MA, Leary ET, et al. Effects of atorvastatin on bone in postmenopausal women with dyslipidemia: a double-blind, placebo-controlled, dose-ranging trial. J Clin Endocrinol Metab 2007;92:4671-7.
33. Wang J, Shang F, Mei Q, Wang J, Zhang R, Wang S. NO-donating genistein prodrug alleviates bone loss in ovariectomised rats. Swiss Med Wkly 2008;138:602-7.
34. Shirazi M, Nilforoushan D, Alghasi H, Dehpour AR. The role of nitric oxide in orthodontic tooth movement in rats. Angle Orthod 2002;72:211-5.
35. Hayashi K, Igarashi K, Miyoshi K, Shinoda H, Mitani H. Involvement of nitric oxide in orthodontic tooth movement in rats. Am J Orthod Dentofacial Orthop 2002;122:306-9.
36. Akin E, Gurton AU, Olmez H. Effects of nitric oxide in orthodontic tooth movement in rats. Am J Orthod Dentofacial Orthop 2004;126:608-14.
37. Talaeipour AR, Shirazi M, Kheirandish Y, Delrobaie A, Jafari F, Dehpour AR. Densitometric evaluation of skull and jaw bones after administration of thyroid hormones in rats. Dentomaxillofac Radiol 2005;34:332-6.
38. Barbosa D, de Souza RA, Xavier M, da Silva FF, Arisawa EA, Villaverde AG. Effects of low-level laser therapy (LLLT) on bone repair in rats: optical densitometry analysis. Lasers Med Sci 2013;28:651-6.
39. Horner K, Devlin H, Alsop CW, Hodgkinson IM, Adams JE. Mandibular bone mineral density as a predictor of skeletal osteoporosis. Br J Radiol 1996;69:1019-25.
| Files | ||
| Issue | Vol 61 No 12 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/acta.v61i12.16369 | |
| Keywords | ||
| Bone density Atorvastatin Ovariectomy Nitric oxide Rats | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Kheirandish Y, Panjnoush M, Babri E, Dehpour AR. Densitometric Evaluation Jaws and Skulls of Ovariectomized Rats Following Atorvastatin Administration: The Role of Nitric Oxide. Acta Med Iran. 2024;61(12):728-735.
