Cyclosporin A Enhances Callus Formation in Rabbit Tibia Fractures

Anders L.  Ekelund; Olle  Nilsson

doi:10.4236/ijcm.2013.47A1005

Anders L. Ekelund, Olle Nilsson^*

Abstract: Purpose: Drugs that modify the production of cytokines may affect fracture healing.The immunosuppressive drug cyclosporin A is widely used to modify the immune response in transplantations and in treatment of rheumatoid disorders. We wanted to analyze the effect of cyclosporin A on fracture healing and on the development of trauma induced osteopenia.Methods: Experimental tibia fractures were stabilised with intramedullary pins in 26 rabbits. The animals were given 5mg/kg/day of cyclosporin A or placebo for 5 weeks. Bone mineral content, callus volume and biomechanical testing were performed on both tibias and femurs.Results: At 5 weeks cyclosporin A treatment resulted in increased bone mineral content and increased callus volume of the fractured bone. The femora on the operated side had significantly lower bone mineral content compared to the non-operated side. This trauma induced osteopenia was unaffected by cyclosporin A treatment. Failure torque and stiffness of the tibia and femora were similar in both groups.Interpretation: Cyclosporin A stimulates bone formation in fracture repair. The mechanism is unclear, but a direct or cytokine mediated effect on bone forming cells, or enhanced bone induction resulting in increased bone formation, is possible.

Keywords: Callus; Cyclosporin A; Osteopenia; Tibia Fractures

Cite this paper: A. Ekelund and O. Nilsson, "Cyclosporin A Enhances Callus Formation in Rabbit Tibia Fractures," International Journal of Clinical Medicine, Vol. 4 No. 7, 2013, pp. 28-33. doi: 10.4236/ijcm.2013.47A1005.

References

[1] A. M. Cueto-Manzabo, S. Konel, V. Crowley, et al., “Bone Hisptopathology and Densitrometry Comparison between Cyclosporine a Monotherapy and Prednisolone Plus Azathioprine Dual Immunosuppression in Renal Transplant Patients,” Transplantation, Vol. 75, No. 12, 2003, pp. 2053-2058. doi:10.1097/01.TP.0000068869.21770.F6

[2] M. Mazzantini, O. Di Munno, L. Sinigaglia, et al., “Effects of Cyclosporine A on Bone Density in Female Rheumatoid Arthritis Patients: Results from a Multicenter Cross-Sectional Study,” Clinical and Experimental Rheumatology, Vol. 25, No. 5, 2007, pp. 700-715.

[3] P. Tannirandorn and S. Epstein, “Drug-Induced Bone Loss,” Osteoporosis International, Vol. 11, No. 8, 2000, pp. 637-659. doi:10.1007/s001980070062

[4] H. M. Frost, “The Biology of Fracture Repair,” Clinical Orthopaedics and Related Research, Vol. 248, 2000, pp. 283-293.

[5] P. Vestergaard, L. Rejnmark and L. Mosekilde, “Methotrexate, Azatioprine, Cyclosporine and Risk of Fracture,” Calcified Tissue International, Vol. 79, No. 2, 2006, pp. 69-75. doi:10.1007/s00223-006-0060-0

[6] M. E. Bolander, “Regulation of Fracture Repair by Growth Factors,” Proceedings of the Society for Experimental Biology and Medicine, Vol. 200, No. 2, 1992, pp. 165170. doi:10.3181/00379727-200-43410A

[7] M. P. G. Bostrom, J. M. Lane, W. S. Berberian, et al., “Immunolocalization and Expression of Bone Morphogenetic Proteins 2 and 4 in Fracture Healing,” Journal of Orthopaedic Research, Vol. 13, No. 3, 1995, pp. 357367. doi:10.1002/jor.1100130309

[8] T. A. Einhorn, “Enhancement of Fracture Healing,” The Journal of Bone & Joint Surgery, Vol. 77, No. 6, 1995, pp. 940-956.

[9] A. Ekelund and O. Nilsson, “Effects of Cyclosporin A on Experimental New Bone Formation in Rats,” Clinical Orthopaedics and Related Research, No. 284, 1992, pp. 288-298.

[10] A. Ekelund and O. Nilsson, “Effects of Cyclosporin A on Bone Turnover and on Resorption of Demineralized Bone Matrix,” Clinical Orthopaedics and Related Research, No. 326, 1996, pp. 127-134. doi:10.1097/00003086-199605000-00015

[11] D. Bunjes, G. Hardt, M. Rollinghoff and H. Wagner, “Cyclosporin A Mediates Immunosuppression of Primary Cytotoxic T Cell Responses by Impairing the Release of Interleukin 1 and Interleukin 2,” European Journal of Immunology, Vol. 11, No. 8, 1981, pp. 657-661. doi:10.1002/eji.1830110812

[12] P. Orcel, J. Bielakoff, D. Modrowski, L. Miravet and M. C. De Vernejoul, “Cyclosporin A Induces in Vivo Inhibition of Resorption and Stimulation of Formation in Rat Bone,” Journal of Bone and Mineral Research, Vol. 4, No. 3, 1989, pp. 387-391. doi:10.1002/eji.1830110812

[13] C. Wada, M. Karaoka, H. Seto, et al., “High-Turnover Osteoporosis Is Induced by Cyclosporin A in Rats,” Journal of Bone and Mineral Metabolism, Vol. 24, No. 3, 2006, pp. 199-205. doi:10.1007/s00774-005-0672-x

[14] G. Movsowitz, S. Epstein, M. Fallon, et al., “Cyclosporin-A in Vivo Produces Severe Osteopenia in the Rat: Effect of Dose and Duration of Administration,” Endocrinology, Vol. 123, No. 5, 1988, pp. 2571-2577. doi:10.1210/endo-123-5-2571

[15] D. Thiebaud, M. A. Krieg, D. Gillard-Berguer, et al., “Cyclosporin Induces High Bone Turnover and May Contribute to Bone Loss after Heart Transplantation,” European Journal of Clinical Investigation, Vol. 26, No. 7, 1996, pp. 549-555. doi:10.1210/endo-123-5-2571

[16] M. Abdelhadi, B. G. Ericzon, K. Hultenby, G. Sjoden, F. P. Reinholt and J. Nordenstrom, “Structural Skeletal Impairment Induced by Immunosupressive Therapy in Rats: Cyclosporine A vs Tacrolimus,” Transplant International, Vol. 15, No. 4, 2002, pp. 180-187. doi:10.1111/j.1432-2277.2002.tb00149.x

[17] T. Ohno, M. Shigetomi, K. Ihara, T. Matsunaga, T. Hashimoto, H. Kawanano, T. Sugiyama and S. Kawai, “Skeletal Reconstruction by Vacularized Allogenic Bone Transplantation: Effects of Statins in Rats,” Transplantation, Vol. 76, No. 5, 2003, pp. 869-871. doi:10.1111/j.1432-2277.2002.tb00149.x

[18] E. Del Pozo and J. Zaff, “Skeletal Growth and Bone Density as Sensitive Parameters in Experimental Arthritis: Effects of Cyclosporin A,” Bone, Vol. 15, No. 6, 1994, pp. 625-628. doi:10.1111/j.1432-2277.2002.tb00149.x

[19] E. Irschik, H. Tilg, D. Niederwieser, G. A. Gastl, et al., “Cyclosporin Blood Levels Do Correlate with Clinical Complications,” Lancet, Vol. 324, No. 8404, 1984, pp. 692-693. doi:10.1111/j.1432-2277.2002.tb00149.x

[20] T. Tsubone, M. Shigetomi, K. Ihara, et al., “Hypertrophy of Vascularized Bone Isografts in Rats Treated with Cyclosporine A,” Calcified Tissue International, Vol. 73, No. 4, 2003, pp. 393-399. doi:10.1111/j.1432-2277.2002.tb00149.x

[21] I. A. Katz, W. S. S. Jee, I. I. Joffe, et al., “Prostaglandin E2 Alleviates Cyclosporin A-Induced Bone Loss in the Rat,” Journal of Bone and Mineral Research, Vol. 7, No. 10, 1992, pp. 1191-1200. doi:10.1111/j.1432-2277.2002.tb00149.x

[22] G. T. Shin, A. Khanna, R. Ding, et al., “In Vivo Expression of Transforming Growth Facto R-Beta 1 in Humans: Stimulation by Cyclosporine,” Transplantation, Vol. 65, No. 3, 1998, pp. 313-318. doi:10.1111/j.1432-2277.2002.tb00149.x

[23] L. Nordsletten, T S. Kaastad, S. Skjeldal, et al., “Fracture Strength Prediction in Rat Femoral Shaft and Neck by Single Photon Absorptiometry of the Femoral Shaft,” Journal of Bone and Mineral Research, Vol. 25, No. 1, 1994, pp. 39-46. doi:10.1111/j.1432-2277.2002.tb00149.x

[24] M. M. Petersen, P. M. Gehrchen, P. K. Nielsen and B. Lund, “Loss of Bone Mineral of the Hip Assessed by DEXA Following Tibial Shaft Fractures,” Bone, Vol. 20, No. 5, 1997, pp. 491-495. doi:10.1111/j.1432-2277.2002.tb00149.x

[25] K. Kawana, M. Takahashi, K. Kushida, et al., “The Effect of Cyclosporin a Administration on Bone Metabolism in the Rat Evaluated by Biomechanical Markers,” Journal of Endocrinological Investigation, Vol. 19, 1996, pp. 499504.