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Anti-osteoporotic effects of melatonin and misoprostol in glucocorticoid-induced osteoporosis: An experimental study

Year 2019, Volume: 3 Issue: 8, 568 - 573, 01.08.2019
https://doi.org/10.28982/josam.595295

Abstract

Aim: Although there are some treatment options for glucocorticoid induced osteoporosis (GIO), new drug alternatives are still needed. In this study, we aimed to determine the protective effects of misoprostol and melatonin in an experimental GIO model.

Methods: The rats were grouped into four, with 10 rats in each group. The 1st group was chosen as the control group, which were not intervened with. Group 2 was the steroid group, group 3 the misoprostol group and group 4, the melatonin group. To the rats in groups 2, 3 and 4, 10 mg/kg subcutaneous methylprednisolone was administered for 28 days. To the rats of the 3rd group, 200 mg/day misoprostol was given per day by a cannula to the stomach. The rats in the 4th group received 5mg/kg intraperitoneal melatonin during this 28-days period. Lumbar vertebrae and femur bone mineral density (BMD) of all rats were measured by Dual-energy X-ray absorptiometry (DEXA) and assessed in pre- and post-treatment periods.

Results: In the steroid group, when the pre- and post-treatment-BMD values of the rats were compared, statistically significant decreases were found in vertebrae, whole femur, femur proximal, femur diaphysis and distal femur bone regions (P=0.011, P=0.005, P=0.007, P=0.005 and P=0.013; respectively). In the misoprostol group, a statistically significant decrease was observed only in the whole femur region (P=0.012) when the pre- and post-treatment BMD values of the rats were compared, while no significant changes were observed in vertebrae, femur proximal, femur diaphysis and distal femur bone regions (P=0.093, P=0.401, P=0.161 and P=0.123; respectively). In the melatonin group, when the pre- and post-treatment BMD values of the rats were compared, a statistically significant decrease was observed only in the vertebrae region (P=0.009), no significant changes were observed in whole femur, femur proximal, femur diaphysis and distal femur bone regions (P=0.386, P=0.445, P=1.000 and P=0.483; respectively). 

Conclusion: Positive effects of misoprostol and melatonin on bone metabolism were determined in this experimental study. Misoprostol and melatonin seem to be potential agents that can be used in the prevention of GIO.

References

  • 1. Weinstein RS. Glucocorticoids, osteocytes, and skeletal fragility: the role of bone vascularity. Bone. 2010;46(3):564-70.
  • 2. Weinstein RS. Glucocorticoid-induced bone disease. N. Engl. J. Med. 2011;365(1):62-70.
  • 3. Achiou Z, Toumi H, Touvier J, Boudenot A, Uzbekov R, Ominsky MS. Sclerostin antibody and interval treadmill training effects in a rodent model of glucocorticoid-induced osteopenia. Bone. 2015;81:691-701.
  • 4. Canali E, Mazziotti G, Giustina A, Bilezikian JP. Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int. 2007;18(10):1319-28.
  • 5. Maricic M, Deal C, Dore R, Laster A. 2017 American college of rheumatology guideline for the prevention and treatment of glucocorticoid-Induced osteoporosis: comment on the article by Buckley et al. Arthritis Care Res (Hoboken). 2018;70(6):949-50.
  • 6. Raisz LG, Woodiel FN. Effects of misoprostol on bone resorption and formation in organ culture. Am J Ther. 1996;3(2):134-8.
  • 7. Milcan A, Colak M, Eskandari G. Misoprostol enhances early fracture healing: a preliminary biochemical study on rats. Bone. 2007;41(4):611-3.
  • 8. Yasar L, Sönmez AS, Utku N, Ozcan J, Cebi Z, Savan K, at al. Effect of misoprostol on bone mineral density in women with postmenopausal osteoporosis.cProstaglandins Other Lipid Mediat. 2006;79(3-4):199-205.
  • 9. Tresguerres IF, Clemente C, Blanco L, Khraisat A, Tamimi F, Tresguerres JA. Effects of local melatonin application on implant osseointegration. Clin Implant Dent Relat Res. 2012;14(3):395-9.
  • 10. Cutando A, Gómez-Moreno G, Arana C, Muñoz F, Lopez-Peña M, Stephenson J, et al. Melatonin stimulates osteointegration of dental implants. J Pineal Res. 2008;45(2):174-9.
  • 11. Manolagas SC. From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis. Endocr Rev. 2010;31(3):266-300.
  • 12. Zhai M, Li B, Duan W, Jing L, Zhang B, Zhang M, et al. Melatonin ameliorates myocardial ischemia reperfusion injury through SIRT3-dependent regulation of oxidative stress and apoptosis. J Pineal Res. 2011;63(2):1-33.
  • 13. Weinstein RS. Glucocorticoid-induced osteoporosis. Rev Endocr Metab Disord. 2001;2:65-73.
  • 14. Mazziotti G, Angeli A, Bilezikian JP, Canalis E, Giustina A. Glucocorticoid-induced osteoporosis: an update. Trends Endocrinol Metab. 2006;17:144-49.
  • 15. Compston J. Glucocorticoid-induced osteoporosis: an update. Endocrine. 2018;61(1):7-16.
  • 16. Sutter S, Nishiyama KK, Kepley A, Wang J, McMahon DJ, Guo XE, at al. Abnormalities in cortical bone, trabecular plates and stiffness in postmenopausal women treated with glucocorticoids. J. Clin. Endocrinol. Metab. 2014;99(11):4231-40.
  • 17. Hulley PA, Conradie MM, Langeveldt CR, Hough FS. Glucocorticoid-induced osteoporosis in the rat is prevented by the tyrosine phosphatase inhibitor, sodium orthovanadate. Bone. 2002;31:220-9.
  • 18. Gruber HE, Hoelscher G, Loeffler B, Chow Y, Ingram JA, Halligan W, et al. Prostaglandin E1 and misoprostol increase epidermal growth factor production in 3D-cultured human annulus cells. Spine J. 2009;9(9):760-6.
  • 19. Gardner CR, Blanqué R, Cottereaux C. Mechanisms involved in prostaglandin-induced increase in bone resorption in neonatal mouse calvaria. Prostaglandins Leukot Essent Fatty Acids. 2001;64(2):117-25.
  • 20. Okman-Kilic T, Sagıroglu C. Anabolik agents as new treatment strategy in osteoporosis.In Flores MV (ed). Topics in Osteoporosis, Rijeka: In tech; 2013. P 241-57.
  • 21. Sonmez AS, Birincioglu M, Ozer MK, Kutlu R, Chuong CJ. Effects of misoprostol on bone loss in ovariectomized rats. Prostaglandins Other Lipid Mediat. 1999;57(2-3):113-8.
  • 22. Ahmet-Camcioglu N, Okman-Kilic T, Durmus-Altun G, Ekuklu G, M. Effects of strontium ranelate, raloxifene and misoprostol on bone mineral density in ovariectomized rats. Eur J Obstet Gynecol Reprod Biol. 2009;147(2):192-4.
  • 23. Koyama H, Nakade O, Takada Y, Kaku T, Lau KH. Melatonin at pharmacologic doses increases bone mass by suppressing resorption through down-regulation of the RANKL-mediated osteoclast formation and activation. J Bone Miner Res. 2002;17(7):1219-29.
  • 24. Sethi S, Radio NM, Kotlarczyk MP, Chen CT, Wei YH, Jockers R, at al. Determination of the minimal melatonin exposure required to induce osteoblast differentiation from human mesenchymal stem cells and these effects on downstream signaling pathways. J Pineal Res. 2010;49(3):222-38.
  • 25. Sharan K, Lewis K, Furukawa T, Yadav VK. Regulation of bone mass through pineal-derived melatonin-MT2 receptor pathway. J Pineal Res. 2017;63(2):1-12.
  • 26. Amstrup AK, Sikjaer T, Pedersen SB, Heickendorff L, Mosekilde L, Rejnmark L. Reduced fat mass and increased lean mass in response to 1 year of melatonin treatment in postmenopausal women: A randomized placebo-controlled trial. Clin Endocrinol. 2016;84(3):342-7.
  • 27. Tresguerres IF, Tamimi F, Eimar H, Barralet JE, Prieto S, Torres J, et al. Melatonin dietary supplement as an anti-aging therapy for age-related bone loss. Rejuvenation Res. 2014;17(4):341-6.
  • 28. Xu L, Zhang L, Wang Z, Li C, Li S, Li L, et al. Melatonin suppresses estrogen deficiency-ınduced osteoporosis and promotes osteoblastogenesis by inactivating the NLRP3 inflammasome. Calcif Tissue Int. 2018;103(4):400-10.
  • 29. Lee S, Le NH, Kang D. Melatonin alleviates oxidative stress-inhibited osteogenesis of human bone marrow-derived mesenchymal stem cells through AMPK activation. Int J Med Sci. 2018;15(10):1083-91.
  • 30. Adams JE. Dual-energy X-ray absorptiometry, In: Guglielmi G, editor. Osteoporosis and bone densitometry measurements. Springer (New York). 2013:101-22.

Glukokortikoid kaynaklı osteoporozda melatonin ve misoprostolün anti-osteoporotik etkileri: Deneysel çalışma

Year 2019, Volume: 3 Issue: 8, 568 - 573, 01.08.2019
https://doi.org/10.28982/josam.595295

Abstract

Amaç: Glukokortikoid kaynaklı osteoporoz için kullanılan bazı tedavi seçenekleri olsa da, yeni ilaç alternatiflerine hâlâ ihtiyaç duyulmaktadır. Çalışmamızda ratlarda glukokortikoid kaynaklı osteoporoz modelinde misoprostol ve melatoninin koruyucu etkilerini belirlemeyi amaçladık.

Yöntemler: Ratlar her grupta 10'ar adet olacak şekilde dört gruba ayrıldı: Grup1 kontrol, grup 2 steroid, grup 3 misoprostol, grup 4 melatonin grubu olarak belirlendi. Grup 2, 3, 4’teki ratlara 28 gün boyunca 10 mg/kg/gün subkutan metilprednizolon uygulandı. Grup 3’teki ratlara ilave olarak 200 mg/gün orogastrik misoprostol, grup 4’teki ratlara ilave olarak 5 mg/kg/intraperitoneal melatonin uygulandı. Tüm ratların lomber vertebra ve femur kemik mineral yoğunluğu DEXA yöntemi ile ölçülerek tedavi öncesi ve sonrası değerler karşılaştırıldı.

Bulgular: Steroid grubunda, çalışma sonrası vertebra, tüm femur, femur proximal, femur diaphysis ve distal femur kemik mineral yoğunluğu değerleri istatistiksel olarak anlamlı derecede düşük bulundu (sırasıyla; P=0,011, P=0,005, P=0,007, P=0,005 ve P=0,013). Misoprostol grubunda sadece tüm femur bölgesinde çalışma sonrası kemik mineral yoğunluğu düşük (P=0,012) olup vertebra, femur proximal, femur diaphysis ve distal femur bölgeleri osteoporozdan korunmuştu (sırasıyla; P=0,093, P=0,401, P=0,161 ve P=0,123). Melatonin grubunda sadece vertebra bölgesinde çalışma sonrası kemik mineral yoğunluğu düşük (P=0,009) olup tüm femur, femur proximal, femur diaphysis ve distal femur bölgelerinde osteoporozdan korunmuştu (sırasıyla; P=0,386, P=0,445, P=1,000 ve P=0,483).

Sonuç: Bu deneysel çalışmada misoprostol ve melatoninin kemik metabolizması üzerindeki olumlu etkileri belirlenmiştir. Misoprostol ve melatonin GIO’nun önlenmesinde kullanılabilecek potansiyel ajanlar gibi görünmektedir.

References

  • 1. Weinstein RS. Glucocorticoids, osteocytes, and skeletal fragility: the role of bone vascularity. Bone. 2010;46(3):564-70.
  • 2. Weinstein RS. Glucocorticoid-induced bone disease. N. Engl. J. Med. 2011;365(1):62-70.
  • 3. Achiou Z, Toumi H, Touvier J, Boudenot A, Uzbekov R, Ominsky MS. Sclerostin antibody and interval treadmill training effects in a rodent model of glucocorticoid-induced osteopenia. Bone. 2015;81:691-701.
  • 4. Canali E, Mazziotti G, Giustina A, Bilezikian JP. Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int. 2007;18(10):1319-28.
  • 5. Maricic M, Deal C, Dore R, Laster A. 2017 American college of rheumatology guideline for the prevention and treatment of glucocorticoid-Induced osteoporosis: comment on the article by Buckley et al. Arthritis Care Res (Hoboken). 2018;70(6):949-50.
  • 6. Raisz LG, Woodiel FN. Effects of misoprostol on bone resorption and formation in organ culture. Am J Ther. 1996;3(2):134-8.
  • 7. Milcan A, Colak M, Eskandari G. Misoprostol enhances early fracture healing: a preliminary biochemical study on rats. Bone. 2007;41(4):611-3.
  • 8. Yasar L, Sönmez AS, Utku N, Ozcan J, Cebi Z, Savan K, at al. Effect of misoprostol on bone mineral density in women with postmenopausal osteoporosis.cProstaglandins Other Lipid Mediat. 2006;79(3-4):199-205.
  • 9. Tresguerres IF, Clemente C, Blanco L, Khraisat A, Tamimi F, Tresguerres JA. Effects of local melatonin application on implant osseointegration. Clin Implant Dent Relat Res. 2012;14(3):395-9.
  • 10. Cutando A, Gómez-Moreno G, Arana C, Muñoz F, Lopez-Peña M, Stephenson J, et al. Melatonin stimulates osteointegration of dental implants. J Pineal Res. 2008;45(2):174-9.
  • 11. Manolagas SC. From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis. Endocr Rev. 2010;31(3):266-300.
  • 12. Zhai M, Li B, Duan W, Jing L, Zhang B, Zhang M, et al. Melatonin ameliorates myocardial ischemia reperfusion injury through SIRT3-dependent regulation of oxidative stress and apoptosis. J Pineal Res. 2011;63(2):1-33.
  • 13. Weinstein RS. Glucocorticoid-induced osteoporosis. Rev Endocr Metab Disord. 2001;2:65-73.
  • 14. Mazziotti G, Angeli A, Bilezikian JP, Canalis E, Giustina A. Glucocorticoid-induced osteoporosis: an update. Trends Endocrinol Metab. 2006;17:144-49.
  • 15. Compston J. Glucocorticoid-induced osteoporosis: an update. Endocrine. 2018;61(1):7-16.
  • 16. Sutter S, Nishiyama KK, Kepley A, Wang J, McMahon DJ, Guo XE, at al. Abnormalities in cortical bone, trabecular plates and stiffness in postmenopausal women treated with glucocorticoids. J. Clin. Endocrinol. Metab. 2014;99(11):4231-40.
  • 17. Hulley PA, Conradie MM, Langeveldt CR, Hough FS. Glucocorticoid-induced osteoporosis in the rat is prevented by the tyrosine phosphatase inhibitor, sodium orthovanadate. Bone. 2002;31:220-9.
  • 18. Gruber HE, Hoelscher G, Loeffler B, Chow Y, Ingram JA, Halligan W, et al. Prostaglandin E1 and misoprostol increase epidermal growth factor production in 3D-cultured human annulus cells. Spine J. 2009;9(9):760-6.
  • 19. Gardner CR, Blanqué R, Cottereaux C. Mechanisms involved in prostaglandin-induced increase in bone resorption in neonatal mouse calvaria. Prostaglandins Leukot Essent Fatty Acids. 2001;64(2):117-25.
  • 20. Okman-Kilic T, Sagıroglu C. Anabolik agents as new treatment strategy in osteoporosis.In Flores MV (ed). Topics in Osteoporosis, Rijeka: In tech; 2013. P 241-57.
  • 21. Sonmez AS, Birincioglu M, Ozer MK, Kutlu R, Chuong CJ. Effects of misoprostol on bone loss in ovariectomized rats. Prostaglandins Other Lipid Mediat. 1999;57(2-3):113-8.
  • 22. Ahmet-Camcioglu N, Okman-Kilic T, Durmus-Altun G, Ekuklu G, M. Effects of strontium ranelate, raloxifene and misoprostol on bone mineral density in ovariectomized rats. Eur J Obstet Gynecol Reprod Biol. 2009;147(2):192-4.
  • 23. Koyama H, Nakade O, Takada Y, Kaku T, Lau KH. Melatonin at pharmacologic doses increases bone mass by suppressing resorption through down-regulation of the RANKL-mediated osteoclast formation and activation. J Bone Miner Res. 2002;17(7):1219-29.
  • 24. Sethi S, Radio NM, Kotlarczyk MP, Chen CT, Wei YH, Jockers R, at al. Determination of the minimal melatonin exposure required to induce osteoblast differentiation from human mesenchymal stem cells and these effects on downstream signaling pathways. J Pineal Res. 2010;49(3):222-38.
  • 25. Sharan K, Lewis K, Furukawa T, Yadav VK. Regulation of bone mass through pineal-derived melatonin-MT2 receptor pathway. J Pineal Res. 2017;63(2):1-12.
  • 26. Amstrup AK, Sikjaer T, Pedersen SB, Heickendorff L, Mosekilde L, Rejnmark L. Reduced fat mass and increased lean mass in response to 1 year of melatonin treatment in postmenopausal women: A randomized placebo-controlled trial. Clin Endocrinol. 2016;84(3):342-7.
  • 27. Tresguerres IF, Tamimi F, Eimar H, Barralet JE, Prieto S, Torres J, et al. Melatonin dietary supplement as an anti-aging therapy for age-related bone loss. Rejuvenation Res. 2014;17(4):341-6.
  • 28. Xu L, Zhang L, Wang Z, Li C, Li S, Li L, et al. Melatonin suppresses estrogen deficiency-ınduced osteoporosis and promotes osteoblastogenesis by inactivating the NLRP3 inflammasome. Calcif Tissue Int. 2018;103(4):400-10.
  • 29. Lee S, Le NH, Kang D. Melatonin alleviates oxidative stress-inhibited osteogenesis of human bone marrow-derived mesenchymal stem cells through AMPK activation. Int J Med Sci. 2018;15(10):1083-91.
  • 30. Adams JE. Dual-energy X-ray absorptiometry, In: Guglielmi G, editor. Osteoporosis and bone densitometry measurements. Springer (New York). 2013:101-22.
There are 30 citations in total.

Details

Primary Language English
Subjects ​Internal Diseases
Journal Section Research article
Authors

Orkide Kutlu 0000-0002-4402-2231

İsa Üzüm This is me 0000-0001-7294-1924

Mustafa Durmuşcan This is me 0000-0001-5960-2848

Ersoy Kekilli This is me 0000-0003-2127-269X

Hakan Parlakpınar This is me 0000-0001-9497-3468

Nurettin Onur Kutlu This is me 0000-0002-3306-6570

Publication Date August 1, 2019
Published in Issue Year 2019 Volume: 3 Issue: 8

Cite

APA Kutlu, O., Üzüm, İ., Durmuşcan, M., Kekilli, E., et al. (2019). Anti-osteoporotic effects of melatonin and misoprostol in glucocorticoid-induced osteoporosis: An experimental study. Journal of Surgery and Medicine, 3(8), 568-573. https://doi.org/10.28982/josam.595295
AMA Kutlu O, Üzüm İ, Durmuşcan M, Kekilli E, Parlakpınar H, Kutlu NO. Anti-osteoporotic effects of melatonin and misoprostol in glucocorticoid-induced osteoporosis: An experimental study. J Surg Med. August 2019;3(8):568-573. doi:10.28982/josam.595295
Chicago Kutlu, Orkide, İsa Üzüm, Mustafa Durmuşcan, Ersoy Kekilli, Hakan Parlakpınar, and Nurettin Onur Kutlu. “Anti-Osteoporotic Effects of Melatonin and Misoprostol in Glucocorticoid-Induced Osteoporosis: An Experimental Study”. Journal of Surgery and Medicine 3, no. 8 (August 2019): 568-73. https://doi.org/10.28982/josam.595295.
EndNote Kutlu O, Üzüm İ, Durmuşcan M, Kekilli E, Parlakpınar H, Kutlu NO (August 1, 2019) Anti-osteoporotic effects of melatonin and misoprostol in glucocorticoid-induced osteoporosis: An experimental study. Journal of Surgery and Medicine 3 8 568–573.
IEEE O. Kutlu, İ. Üzüm, M. Durmuşcan, E. Kekilli, H. Parlakpınar, and N. O. Kutlu, “Anti-osteoporotic effects of melatonin and misoprostol in glucocorticoid-induced osteoporosis: An experimental study”, J Surg Med, vol. 3, no. 8, pp. 568–573, 2019, doi: 10.28982/josam.595295.
ISNAD Kutlu, Orkide et al. “Anti-Osteoporotic Effects of Melatonin and Misoprostol in Glucocorticoid-Induced Osteoporosis: An Experimental Study”. Journal of Surgery and Medicine 3/8 (August 2019), 568-573. https://doi.org/10.28982/josam.595295.
JAMA Kutlu O, Üzüm İ, Durmuşcan M, Kekilli E, Parlakpınar H, Kutlu NO. Anti-osteoporotic effects of melatonin and misoprostol in glucocorticoid-induced osteoporosis: An experimental study. J Surg Med. 2019;3:568–573.
MLA Kutlu, Orkide et al. “Anti-Osteoporotic Effects of Melatonin and Misoprostol in Glucocorticoid-Induced Osteoporosis: An Experimental Study”. Journal of Surgery and Medicine, vol. 3, no. 8, 2019, pp. 568-73, doi:10.28982/josam.595295.
Vancouver Kutlu O, Üzüm İ, Durmuşcan M, Kekilli E, Parlakpınar H, Kutlu NO. Anti-osteoporotic effects of melatonin and misoprostol in glucocorticoid-induced osteoporosis: An experimental study. J Surg Med. 2019;3(8):568-73.