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The effects of pentoxifylline adminstration on fracture healing in a postmenopausal osteoporotic rat model
Laboratory Animal Research volume 33, pages 15–23 (2017)
Previous studies report positive effects of pentoxifylline (PTX) alone or in combination with other drugs on some pathologic bone diseases as well as an ability to accelerate osteogensis and fracture healing in both animal models and human patients. The aim of this present study was to evaluate the effects of PTX administration on Hounsfield unit and bone strength at catabolic response (bone resorbing) of a fracture in an experimental rat model of ovariectomy induced osteoporosis (OVX-D). Thirty adult female rats were divided into groups as follows: 1 (OVX, control, no treatment); 2 (OVX, sham: daily distilled water); 3 (OVX, daily alendronate: 3 mg/kg); 4 (OVX, twice daily 100 mg/kg PTX) and 5 (OVX, PTX+alenderonate). OVX was induced by bilateral ovariectomy in all rats. A complete standardized osteotomy of the right femur was made after 3.5 months. PTX and alendronate treatments were performed for eight weeks. Then, rats were euthanized and had its right femur subjected to computerized tomography scanning for measuring Hounsfield unit; eventually, the samples were sent for a three point bending test for evaluation of the bone strength. Administration of PTX with 200 mg/kg and alendronate alone and in combination showed no significant alteration in Hounsfield unit and biomechanical properties of repairing callus of the complete osteotomy compared with the control group. Results showed increased bending stiffness and stress high load mean values of repairing complete osteotomy in PTX-treated rats compared to the control OVX-D.
Ozgediz D, Chu K, Ford N, Dubowitz G, Bedada AG, Azzie G, Gerstle JT, Riviello R. Surgery in global health delivery. Mt Sinai J Med 2011; 78(3): 327–341.
Mock C, Cherian MN. The global burden of musculoskeletal injuries: challenges and solutions. Clin Orthop Relat Res 2008; 466(10): 2306–2316.
Bandela V, Munagapati B, Karnati RK, Venkata GR, Nidudhur SR. Osteoporosis: Its Prosthodontic Considerations-A Review. J Clin Diagn Res 2015; 9(12): ZE01–4.
Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 2006; 17(12): 1726–1733.
Ray NF, Chan JK, Thamer M, Melton LJ 3rd. Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. J Bone Miner Res 1997; 12(1): 24–35.
Tajeu GS, Delzell E, Smith W, Arora T, Curtis JR, Saag KG, Morrisey MA, Yun H, Kilgore ML. Death, debility, and destitution following hip fracture. J Gerontol A Biol Sci Med Sci 2014: 69(3): 346–353.
Pothiwala P, Evans EM, Chapman- Novakofski KM. Ethnic variation in risk for osteoporosis among women: a review of biological and behavioral factors. J Womens Health (Larchmt) 2006; 15(6): 709–719.
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.
Ralston SH. Analysis of gene expression in human bone biopsies by polymerase chain reaction: evidence for enhanced cytokine expression in postmenopausal osteoporosis. J Bone Miner Res 1994; 9(6): 883–890.
Kinoshita T, Kobayashi S, Ebara S, Yoshimura Y, Horiuchi H, Tsutsumimoto T, Wakabayashi S, Takaoka K. Phosphodiesterase inhibitors, pentoxifylline and rolipram, increase bone mass mainly by promoting bone formation in normal mice. Bone 2000; 27(6): 811–817.
Ahlström M, Lamberg- Allardt C. Rapid protein kinase A—mediated activation of cyclic AMP-phosphodiesterase by parathyroid hormone in UMR-106 osteoblast-like cells. J Bone Miner Res 1997; 12(2): 172–178.
ivitelli R, Bacskai BJ, Mahaut-Smith MP, Adams SR, Avioli LV, Tsien RY. Single-cell analysis of cyclic AMP response to parathyroid hormone in osteoblastic cells. J Bone Miner Res 1994; 9(9): 1407–1417.
Wronski TJ, Yen CF, Qi H, Dann LM. Parathyroid hormone is more effective than estrogen or bisphosphonates for restoration of lost bone mass in ovariectomized rats. Endocrinology 1993; 132(2): 823–831.
Degerman E, Smith CJ, Tornqvist H, Vasta V, Beifrage P, Manganiello VC. Evidence that insulin and isoprenaline activate the cGMP-inhibited low-Km cAMP phosphodiesterase in rat fat cells by phosphorylation. Proc Natl Acad Sci USA 1990; 87(2): 533–537.
Marchmont RJ, Ayad SR, Houslay MD. Purification and properties of the insulin-stimulated cyclic AMP phosphodiesterase from rat liver plasma membranes. Biochem J 1981; 195(3): 645–652.
Bayat M, Amini A, Rezaie F, Bayat S. Patents of Pentoxifylline Administration on some diseases and chronic wounds. Recent Patents on Regenerative Medicine 2014; 4(2): 137–143.
Vashghani Farahani MM, Masteri Farahani R, Mostafavinia A, Abbasian MR, Pouriran R, Noruzian M, Ghoreishi SK, Aryan A, Bayat M. Effect of Pentoxifylline Administration on an Experimental Rat Model of Femur Fracture Healing With Intramedullary Fixation. Iran Red Crescent Med J 2015; 17(12): e29513.
Çakmak G, Þahin MÞ, Özdemİr BH, Karadenİz E. Effect of pentoxifylline on healing of segmental bone defects and angiogenesis. Acta Orthop Traumatol Turc 2015; 49(6): 676–682.
Atalay Y, Gunes N, Guner MD, Akpolat V, Celik MS, Guner R. Pentoxifylline and electromagnetic field improved bone fracture healing in rats. Drug Des Devel Ther 2015; 9: 5195–5201.
Bohn JC, Schussel JL, Stramandinoli-Zanicotti RT, Sassi LM. Tissue repair in osteoradionecrosis using pentoxifylline and tocopherol—report of three cases. Oral Maxillofac Surg 2016; 20(1): 97–101.
Erken HY, Burc H, Aydogan M. The Effect of Pentoxifylline on Spinal Fusion: An Experimental Study in Rabbits. Spine (Phila Pa 1976) 2014; 39;(11): 27.
Labib GS, Farid RM. Osteogenic effect of locally applied Pentoxyfilline gel: in vitro and in vivo evaluations. Drug Deliv 2015; 22(8): 1094–1102.
Queiroz-Junior CM, Bessoni RL, Costa VV, Souza DG, Teixeira MM, Silva TA. Preventive and therapeutic anti-TNF-α therapy with pentoxifylline decreases arthritis and the associated periodontal co-morbidity in mice. Life Sci 2013; 93(9-11): 423–428.
Aydin K, Sahin V, Gürsu S, Mercan AS, Demir B, Yildirim T. Effect of pentoxifylline on fracture healing: an experimental study. Eklem Hastalik Cerrahisi 2011; 22(3): 160–165.
Wei T, Sabsovich I, Guo TZ, Shi X, Zhao R, Li W, Geis C, Sommer C, Kingery WS, Clark DJ. 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.
Horiuchi H, Saito N, Kinoshita T, Wakabayashi S, Tsutsumimoto T, Otsuru S, Takaoka K. Enhancement of recombinant human bone morphogenetic protein-2 (rhBMP-2)-induced new bone formation by concurrent treatment with parathyroid hormone and a phosphodiesterase inhibitor, pentoxifylline. J Bone Miner Metab 2004; 22(4): 329–334.
Beþe NS, Ozgüroğlu M, Kamberoğlu K, Karahasanoglu T, Ober A. Pentoxifylline in the treatment of radiation-related pelvic insufficiency fractures of bone. Radiat Med 2003; 21(5): 223–227.
Robin JC, Ambrus JL. Study of antiosteoporotic agents in tissue culture. J Med 1984; 15(4): 319–322.
Robin JC, Ambrus JL. Studies on osteoporoses. XI. Effects of a methylxanthine derivative. A preliminary report. J Med 1983; 14(2): 137–145.
Magremanne M, Reychler H. Pentoxifylline and tocopherol in the treatment of yearly zoledronic acid-related osteonecrosis of the jaw in a corticosteroid-induced osteoporosis. J Oral Maxillofac Surg 2014; 72(2): 334–337.
Takami M, Cho ES, Lee SY, Kamijo R, Yim M. Phosphodiesterase inhibitors stimulate osteoclast formation via TRANCE/RANKL expression in osteoblasts: possible involvement of ERK and p38 MAPK pathways. FEBS Lett 2005; 579(3): 832–838.
Hosny KM. Alendronate sodium as enteric coated solid lipid nanoparticles; preparation, optimization, and in vivo evaluation to enhance its oral bioavailability. PLoS One 2016; 11(5): e0154926.
Imai K. Alendronate sodium hydrate (oral jelly) for the treatment of osteoporosis: review of a novel, easy to swallow formulation. Clin Interv Aging 2013; 8: 681–688.
Mostafavinia A, Ahadi R, Abdollahifar MA, Ghorishi SK, Jalalifirouzkouhi A, Bayat M. Evaluation of the Effects of Low-Level Laser Therapy on Biomechanical Properties and Hounsfield Unit of Partial Osteotomy Healing in an Experimental Rat Model of Type I Diabetes and Osteoporosis under publication. DOI: 10.1089/pho.2016.4191.
Lee SW, Jeon TJ, Biswal S. Fracture Healing Effects of Locally-Administered Adipose Tissue-Derived Cells. Yonsei Med J 2015; 56(4): 1106–1113.
Little DG, Ramachandran M, Schindeler A. The anabolic and catabolic responses in bone repair. J Bone Joint Surg Br 2007; 89(4): 425–433.
Caro AC, Tucker JJ, Yannascoli SM, Dunkman AA, Thomas SJ, Soslowsky LJ. Efficacy of various analgesics on shoulder function and rotator cuff tendon-to-bone healing in a rat (Rattus norvegicus) model. J Am Assoc Lab Anim Sci 2014; 53(2): 185–192.
Freidouni M, Nejati H, Salimi M, Bayat M, Amini A, Noruzian M, Asgharie MA, Rezaian M. Evaluating glucocorticoid administration on biomechanical properties of rats’ tibial diaphysis. Iran Red Crescent Med J 2015; 17(3): e19389.
Renno AC, de Moura FM, dos Santos NS, Tirico RP, Bossini PS, Parizotto NA. Effects of 830-nm laser, used in two doses, on biomechanical properties of osteopenic rat femora. Photomed Laser Surg 2006; 24(2): 202–206.
Ibrahim N, Mohamed N, Shuid AN. Update on statins: hope for osteoporotic fracture healing treatment. Curr Drug Targets 2013; 14(13): 1524–1532.
Lewiecki EM. New targets for intervention in the treatment of postmenopausal osteoporosis. Nat Rev Rheumatol 2011; 7(11): 631–638.
Bayat M, Chelcheraghi F, Piryaei A, Rakhshan M, Mohseniefar Z, Rezaie F, Bayat M, Shemshadi H, Sadeghi Y. The effect of 30-day pretreatment with pentoxifylline on the survival of a random skin flap in the rat: an ultrastructural and biomechanical evaluation. Med Sci Monit 2006; 12(6): BR201–207.
Velaei K, Bayat M, Torkman G, Rezaie F, Amini A, Noruzian M, Tavassol A, Bayat M. Evaluating the effects of pentoxifylline administration on experimental pressure sores in rats by biomechanical examinations. Lab Anim Res 2012; 28(3): 209–215.
Babaei S, Bayat M, Nouruzian M, Bayat M. Pentoxifylline improves cutaneous wound healing in streptozotocin-induced diabetic rats. Eur J Pharmacol 2013; 700(1-3): 165–172.
Babaei S, Bayat M. Pentoxifylline Accelerates Wound Healing Process by Modulating Gene Expression of MMP-1, MMP-3, and TIMP-1 in Normoglycemic Rats. J Invest Surg 2015; 28(4): 196–201.
Luger EJ, Rochkind S, Wollman Y, Kogan G, Dekel S. Effect of low-power laser irradiation on the mechanical properties of bone fracture healing in rats. Lasers Surg Med 1998; 22(2): 97–102.
Ammann P, Rizzoli R. Bone strength and its determinants. Osteoporos Int 2003; 14 Suppl 3: S13–18.
Ammann P. [Determining factors of bone mechanical resistance]. Therapie 2003; 58(5): 403–407.
Wakabayashi S, Tsutsumimoto T, Kawasaki S, Kinoshita T, Horiuchi H, Takaoka K. Involvement of phosphodiesterase isozymes in osteoblastic differentiation. J Bone Miner Res 2002; 17(2): 249–256.
Rawadi G, Ferrer C, Spinella-Jaegle S, Roman-Roman S, Bouali Y, Baron R. 1-(5-oxohexyl)-3,7-Dimethylxanthine, a phosphodiesterase 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.
McLeod NM, Pratt CA, Mellor TK, Brennan PA. Pentoxifylline and tocopherol in the management of patients with osteoradionecrosis, the Portsmouth experience. Br J Oral Maxillofac Surg 2012; 50(1): 41–44.
Bilezikian JP. Efficacy of bisphosphonates in reducing fracture risk in postmenopausal osteoporosis. Am J Med 2009; 122(2 Suppl): S14–21.
Kolios L, Hoerster AK, Sehmisch S, Malcherek MC, Rack T, Tezval M, Seidlova-Wuttke D, Wuttke W, Stuermer KM, Stuermer EK. Do estrogen and alendronate improve metaphyseal fracture healing when applied as osteoporosis prophylaxis? Calcif Tissue Int 2010; 86(1): 23–32.
We wish to extend our sincere thanks to the late Mrs. Jamileh Rezaei. This article had fmancially supported from the Research Department of Shahid Beheshti University of Medical Sciences, Tehran, Iran (grant no 1392-1-115-1159).
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Vashghani Farahani, M.M., Ahadi, R., Abdollahifar, M. et al. The effects of pentoxifylline adminstration on fracture healing in a postmenopausal osteoporotic rat model. Lab Anim Res 33, 15–23 (2017). https://doi.org/10.5625/lar.2017.33.1.15
- hounsfield unit biomechanical phenomena