Effects of pentoxifylline and alendronate on fracture healing in ovariectomy-induced osteoporosis in rats

Document Type: Original Article

Authors

1 Department of Basic Sciences, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

2 Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Science, Tehran, Iran

3 Cellular and Molecular Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran

4 Department of Statistics, Faculty of Sciences, University of Qom, Qom, Iran

5 Department of Internal Medicine, Aurora Medical Center- Bay Area, Marinette, Wisconsin, USA

6 Price Institute of Surgical Research, University of Louisville, Noveratech LLC of Louisville, Louisville, USA

7 Department of Anatomy, School of Medicine, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran

8 Cellular and Molecular Biology Research Center, Department of Biology and Anatomical Sciences, Shahid Beheshti University of Medical Science, Tehran, Iran

Abstract

Osteoporosis is determined by decreased bone strength that increases the threat of fractures. The aim of this study was to evaluate the effects of pentoxifylline (PTX) and alendronate (ALN), on the stereological parameters, and gene expression in callus of fracture in an experimental rat model of ovariectomy-induced osteoporosis (OVX). The OVX was induced in 90 female rats. Fourteen weeks later, a complete fracture on the right femur was made. Rats were divided into five groups: 1) control: no treatment; 2) sham: received daily distilled water; 3) daily 3.00 mg kg-1 ALN subcutaneously (SC); 4) daily 200 mg kg-1 PTX (SC) and 5) daily PTX (SC) + ALN (same doses). The osteoclast count was significantly lower in all treatment groups, at 21 and 56 days post-surgery, compared to the control and sham groups. The PTX significantly increased total callus volume at 21 and 56 days post-surgery, compared to the other groups. The PTX+ALN treatment significantly increased both cortical bone volume on day 21, and osteocyte and osteoblast numbers on day 56, compared to the control and sham groups. It can be concluded that PTX and ALN have antiresorptive effects, in OVX rats. Also, PTX has increased the extracellular matrix on both 21 and 56 days after surgery, compared to the other groups. PTX+ALN elevated cortical bone volume on day 21, and osteocyte and osteoblast numbers compared to the control and sham groups on day 56.

Keywords

Main Subjects

 

  1. Hagenfeldt K, Johansson C, Johnell O, et al. Osteoporosis – prevention, diagnosis and treatment: A systematic review. Available at: https://www.sbu.se/en/publications/sbu-assesses/osteoporosis prevention diagnosis and treatment/.html. Accessed Jul 01, 2018.
  2. Curtis JR, Safford MM. Management of osteoporosis among the elderly with other chronic medical conditions. Drugs Aging 2012; 29(7): 549-564.
  3. National Osteoporosis Foundation. Fast facts on osteoporosis. Available at: http://www.nof.org/ osteoporosis/diseasefacts.html. Accessed Jul 01, 2018.
  4. Burge R, Dawson-Hughes B, Solomon DH, et al. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res 2007;22(3): 465-475.
  5. Riggs BL, Khosla S, Melton LJ. A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res 1998;13(5): 763-773.
  6. Manolagas SC. Birth and death of bone cells: Basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 2000;21(2): 115-137.
  7. Feron JM, Mauprivez R. Fracture repair: General aspects and influence of osteoporosis and anti-osteo-porosis treatment. Injury 2016; 47 (Suppl 1): S10-S14.
  8. Goldhahn J, Scheele WH, Mitlak BH, et al. Clinical evaluation of medicinal products for acceleration of fracture healing in patients with osteoporosis. Bone 2008; 43(2):343-347.
  9. Kates SL, Ackert-Bicknell CL. How do bisphosphonates affect fracture healing? Injury 2016;47 (S1): S65-S68.
  10. Cao Y, Mori S, Mashiba T, et al. Raloxifene, estrogen, and alendronate affect the processes of fracture repair differently in ovariectomized rats. J Bone Miner Res 2002;17(12): 2237-2246.
  11. Saito M, Shiraishi A, Ito M, et al. Comparison of effects of alfacalcidol and alendronate on mechanical properties and bone collagen cross-links of callus in the fracture repair rat model. Bone 2010;46(4): 1170-1179.
  12. Sloan AV, Martin JR, Li S, et al. Parathyroid hormone and bisphosphonate have opposite effects on stress fracture repair. Bone 2010;47(2):235-240.
  13. Aonuma H, Miyakoshi N, Kasukawa Y, et al. Combined treatment of alendronate and low-intensity pulsed ultrasound (LIPUS) increases bone mineral density at the cancellous bone osteotomy site in aged rats: A preliminary study. JNMA J Nepal Med Assoc 2011;51(184):171-175.
  14. Fu LJ, Tang TT, Hao YQ, et al. Long-term effects of alendronate on fracture healing and bone remodeling of femoral shaft in ovariectomized rats. Acta Pharmacol Sin 2013;34(3):387-392.
  15. Pountos I, Georgouli T, Blokhuis TJ, et al. Pharmaco-logical agents and impairment of fracture healing: what is the evidence? Injury 2008;39(4):384-394.
  16. Vashghani-Farahani MM, Masteri-Farahani R, Mostafavinia A, et al. Effect of pentoxifylline administration on an experimental rat model of femur fracture healing with intramedullary fixation. Iran Red Crescent Med J 2015 28;17(12):e29513.
  17. Atalay Y, Gunes N, Guner MD, et al. Pentoxifylline and electromagnetic field improved bone fracture healing in rats. Drug Des Devel Ther 2015; 9:5195-5201.
  18. Aydin K, Sahin V, Gursu S, et al. Effect of pentoxifylline on fracture healing: an experimental study. Eklem Hastalik Cerrahisi 2011;22(3):160-165.
  19. Erken HY, Burc H, Aydogan M. The Effect of Pentoxify-lline on spinal fusion: An experimental study in rabbits. Spine (Phila Pa 1976). 2014; 39(11): E676-E683.
  20. Wei T, Sabsovich I, Guo TZ, et al. Pentoxifylline attenuates nociceptive sensitization and cytokine expression in a tibia fracture rat model of complex regional pain syndrome. Eur J Pain 2009;13
    (3):253-262.
  21. Beşe NS, Ozguroglu M, Kamberoglu K, et al. Pentoxifylline in the treatment of radiation-related pelvic insufficiency fractures of bone. Radiat Med 2003;21(5):223-227.
  22. Vashghani-Farahani MM, Ahadi R, Abdollahifar M, et al. The effects of pentoxifylline adminstration on fracture healing in a postmenopausal osteoporotic rat model. Lab Anim Res 2017;33(1):15-23.
  23. Mostafavinia A, Farahani RM, Abbasian M, et al. Effect of pulsed wave low-level laser therapy on tibial complete osteotomy model of fracture healing with an intramedullary fixation. Iran Red Crescent Med J 2015;17(12):e32076.
  24. Little DG, Ramachandran M, Schindeler A. The anabolic and catabolic responses in bone repair. J Bone Joint Surg Br 2007;89 (4):425-433.
  25. Bagi C, vander Meulen M, Brommage R, et al. The effect of systemically adminsterated rh IGF-I/IGFBP-3 complex on cortical bone strength and structure in ovariectomized rats. Bone 1995;16(5):559-565.
  26. Li X, Ominsky MS, Warmington KS. et al. Increased bone formation and bone mass induced by sclerostin antibody is not affected by pretreatment or co-treatment with alendronate in osteopenic, ovariectomized rats. Endocrionology 2011;152 (9):3312-3322.
  27. Allen HL, Wase A, Bear WT. Indomethacin and aspirin: Effect of nonsteroidal anti-inflammatory agents on the rate of fracture repair in the rat. Acta Orthop Scand 1980;51(4):595-600.
  28. Stuermer EK, Sehmisch S, Rack T, et al. Estrogen and raloxifene improve metaphyseal fracture healing in the early phase of osteoporosis. A new fracture-healing model at the tibia in rat. Langenbecks Arch Surg 2010;395(2):163-172.
  29. Fredoni M, Ghatrehsamani M, Abdollahifar MA, et al. Evaluation of the effects of photobiomodulation on vertebras in two rat models of experimental osteoporosis. Lasers Med Sci 2017;32(7):1545-1560.
  30. Dean DB, Watson JT, Jin W, et al. Distinct functionalities of bone morphogenetic protein antagonists during fracture healing in mice. J Anat 2010;216(5):625-630.
  31. Kakar S, Einhorn TA, Vora S. Enhanced chondrogenesis and Wnt signaling in PTH-treated fractures. J Bone Miner Res 2007;22(12):1903-1912.
  32. Pazianas M, van der Geest S, Miller P. Bisphosphonates and bone quality. Bonekey Rep 2014;3:529.
  33. D'Amelio P1, Grimaldi A, Cristofaro MA, et al. Alendronate reduces osteoclast precursors in osteoporosis. Osteoporos Int 2010;21(10):1741-1750.
  34. Kinoshita T, Kobayashi S, Ebara S, et al. Phospho-diesterase inhibitors, pentoxifylline and rolipram, increase bone mass mainly by promoting bone formation in normal mice. Bone 2000;27(6):811-817.
  35. Wakabayashi S, Tsutsumimoto T, Kawasaki S, et al. Involvement of phosphodiesterase isozymes in osteoblastic differentiation. J Bone Miner Res 2002;17(2):249-256.
  36. Rawadi G, Ferrer C, Spinella-Jaegle S, et al. 1-(5-oxohexyl)-3,7-Dimethylxanthine, a phospho-diesterase inhibitor, activates MAPK cascades and promotes osteoblast differentiation by a mechanism independent of PKA activation (pentoxifylline promotes osteoblast differentiation). Endocrinology 2001;142(11):4673-4682.
  37. Kawai VK, Stein CM, Perrien DS, et al. Effects of anti-tumor necrosis factor α agents on bone. Curr Opin Rheumatol 2012;24(5):576-585.
  38. Kimble RB, Bain S, Pacifici R. The functional block of TNF but not of IL-6 prevents bone loss in ovariectomized mice. J Bone Miner Res 1997; 12(6):935-941.
  39. Schandené L, Vandenbussche P, Crusiaux A, et al. Differential effects of pentoxifylline on the production of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) by monocytes and T cells. Immunology 1992;76(1):30-34.
  40. D'Hellencourt CL, Diaw L, Cornillet P, et al. Differential regulation of TNF alpha, IL-1 beta, IL-6, IL-8, TNF beta, and IL-10 by pentoxifylline. Int J Immunopharmacol 1996;18(12):739-748.
  41. Çakmak G, Şahin MŞ, Ozdemİr BH, et al. Effect of pentoxifylline on healing of segmental bone defects and angiogenesis. Acta Orthop Traumatol Turc 2015;49(6):676-682.
  42. Shimizu K, Yoshikawa H, Matsui M, et al. Periosteal and intratumorous bone formation in athymic nude mice by Chinese hamster ovary tumors expressing murine bone morphogenetic protein-4. Clin Orthop Relat Res 1994;(300):274-280.
  43. Lee YS, Chuong CM. Activation of protein kinase A is a pivotal step involved in both BMP-2- and cyclic AMP-induced chondrogenesis. J Cell Physiol 1997;170 (2):153-165.
  44. Iolascon G, Frizzi L, Di Pietro G, et al. Bone quality and bone strength: Benefits of the bone-forming approach. Clin Cases Miner Bone Metab 2014;11(1):20-24.