Effects of internal fixation with simvastatin coating on healing of rat osteoporotic fractures at late period

doi:10.3969/j.issn.2095-4344.2013.51.008

Abstract

Abstract:

BACKGROUND: As a lipid-lowering drug, simvastatin has been proved to be effective in promoting bone formation. Previous studies have demonstrated that locally applied simvastation accelerated fracture healing at middle phase in osteoporotic rats, while no study focuses on the influence of locally applied simvastatin on fracture healing at late period in an osteoporotic rat.
OBJECTIVE: To investigate the effect of simvastatin locally applied from a bioactive polymer coating of implants on osteoporotic fracture healing at late period.
METHODS: Female Sprague-Dawley rats were divided into sham group, osteoporotic fracture group and simvastatin group. In the sham group, the abdominal cavity was exposed without ovariectomy. Six weeks later, femur fracture models were established in normal or osteotoporotic Sprague-Dawley rats, and intramedullary stabilization was achieved with uncoated titanium Kirschner wires in normal rats (sham group),with polylactic acid coated titanium Kirschner wires (osteoporotic fracture group) and with simvastatin/polylactic acid coated titanium Kirschner wires (simvastatin group). Femurs were harvested after 12 weeks, bone mineral density was determined with dual X-ray absorptiometry, and then radiographic and histological analysis was performed for analysis of fracture healing. Immunohistochemical evaluation was employed for bone morphogenetic protein 2 expression.
RESULTS AND CONCLUSION: The bone mineral densities of both the total fractured femur and fractured site 12 weeks after fracture in the osteoporotic fracture group and simvastatin group were markedly decreased compared to normal fractured rats. The bone mineral density of the fractured site was significantly higher in the simvastatin group than the osteoporotic fracture group. Radiographic results demonstrated completely finished callus remodeling in the sham group; poor healing, pale callus density and blurred fracture line were seen in the osteoporotic fracture group; disappearance of fracture line, bone defects filled with callus, and deep periosteal reaction were found in the simvastatin group. X-ray scores in the sham and simvastatin groups were significantly higher than that in the osteoporotic group (P < 0.05). Hematoxylin-eosin staining showed a delayed healing process in the osteoporotic group, and revealed a significantly processed callus with regular-shaped newly formed bone trabeculae in the simvastatin group. Immunohistochemical evaluation showed no significant difference in the bone morphogenetic protein 2 expression between any two groups. These findings suggest an improved fracture healing under local application of simvastatin in osteoporotic rats.

中国组织工程研究杂志出版内容重点：生物材料；骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性；组织工程

全文链接：

Key words: osteoporosis, fracture healing, bone density, periosteum, bone morphogenetic proteins

CLC Number:

R318

Xi Guang-wei, Wang Xue-ling, Gong Lin, Meng Xian-min, Zhang Jun-shan, Tian Fa-ming. Effects of internal fixation with simvastatin coating on healing of rat osteoporotic fractures at late period[J]. Chinese Journal of Tissue Engineering Research, 2013, 17(51): 8827-8833.

Figures/Tables 4

References

[1]Mundy G, Garrett R, Harris S, et al. Stimulation of bone formation in vitro and in rodents by statins. Science. 1999; 286(5446): 1946-1949.

[2]Oxlund H, Andreassen TT. Simvastatin treatment partially　ovariectomy- induced bone loss while increasing cortical　bone formation. Bone. 2004;34(4): 609-618.

[3]Pauly S, Luttosch F, Morawski M, et al. simvastatin locally applied from biodegradable coating of osteosynthetic implants in improves fracture healing coparable to BMP-2 application. Bone. 2009;45(3): 505-511.

[4]张俊山, 田发明, 康玉川, 等.高生物涂层局部应用辛伐他汀对骨质疏松大鼠骨折愈合的影响[J].第三军医大学学报, 2013, 53(12): 1274-1278.

[5]Saville PD. Changes in skeletal mass and fragility with castration in the rat: a model of osteoporosis. J Am Geriatr Soc.1969;17(2):155-166.

[6]田发明, 张柳, 骆阳, 等.仙灵骨葆对骨质疏松性骨折骨痂血管形成的影响[J].中国组织工程研究与临床康复, 2011, 15(32): 5913-5917.

[7]田发明,张柳,骆阳,等.辛伐他汀对大鼠骨质疏松性骨折愈合的影响[J].中国药学杂志,2012,47(21):1719-1723.

[8]崔永锋,王琦,张毅,等.杜仲对兔骨折愈合影响的X线影像学研究[J].中药新药与临床药理,2003,14(3):163-165.

[9]Boeloni JN, Ocarino NM, Goes AM, et al. Comparative study of osteogenic differentiation potential of mesenchymal stem cells derived from bone marrow and adipose tissue of osteoporotic female rats. Connect Tissue Res. 2013. [Epub ahead of print]

[10]Smith BJ, Bu SY, Wang Y, et al.A comparative study of the bone metabolic response to dried plum supplementation and PTH treatment in adult, osteopenic ovariectomized rat. Bone. 2013. [Epub ahead of print]

[11]Zhao H, Li X, Li N, et al. Long-term resveratrol treatment prevents ovariectomy-induced osteopenia in rats without hyperplastic effects on the uterus. Br J Nutr. 2013:1-11.

[12]Zhao B, Wang Q, Tao T, et al. The in vitro and in vivo treatment effects of overexpressed lentiviral vector-mediated human BMP2 gene in the femoral bone marrow stromal cells of osteoporotic rats. Int J Mol Med. 2013;32(6):1355-1365.

[13]Zhang LZ, Xin JL, Zhang XP, et al. The anti-osteoporotic effect of velvet antler polypeptides from Cervus elaphus Linnaeus in ovariectomized rats. J Ethnopharmacol. 2013; 150(1):181-186.

[14]Nikolaou VS, Efstathopoulos N, Kontakis G, et al. The influence of osteoporosis in femoral fracture healing time. Injury. 2009;40(6):663-668.

[15]Kubo T, Shiga T, Hashimoto J,et al. Osteoporosis influences the late period of fracture healing in a rat model prepared by ovariectomy and low calcium diet. J Steroid Biochem Mol Biol.1999; 68(5-6):197-202.

[16]Wang JW, Li W, Xu SW, et al.osteoporosis influences the middle and late periods of fracture healing in a rat osteoporotic model. Chin J Traumatology. 2005; 8(2): 111-116.

[17]乔林, 徐克惠, 刘宏伟, 等.去势对雌性大鼠骨折愈合影响的实验研究[J].四川大学学报:医学版,2005,36(1):108-111.

[18]Hao YJ, Zhang G, Wang YS, et al.Changes of microstructure and mineralized tissue in the middle and late phase of osteoporotic fracture healing in rats.Bone.2007;41(4): 631-638.

[19]Tarantino U, Cerocchi I, Scialdoni A, et al. Bone healing and osteoporosis. Aging Clin Exp Res. 2011;23(2s):62-64.

[20]Cao Y, Mori S, Mashiba T, et al. estrogen and alendronate affect the processes of fracture repair differently in ovariectomized rats. J Bone Miner Res. 2002; 17 (12): 2237-2246.

[21]Manabe T, Mori S, Mashiba T, et al. Eel calcitonin (elcatonin) suppressed callus remodeling but did not interfere with fracture healing in the femoral fracture model of cynomolgus monkeys. J Bone Miner Metab. 2009; 27(3): 295-302.

[22]Rejnmark L, Olsen ML, Johnsen SP, et al. Hip fracture risk in statin users--a population-based Danish case-control study. Osteoporos Int.2004; 15(6): 452-458.

[23]Nguyen ND, Wang CY, Eisman JA, et al. On the association between statin and fracture: a Bayesian consideration. Bone. 2007; 40(4):813-820.

[24]Nichols R, Hopman WM, Morton AR, et al. Statins are associated with a reduced risk of bone fracture in hemodialysis (HD) patients, Hemodial Int. 2008;12(2): 275- 279.

[25]Helin-Salmivaara A, Korhonen MJ, Lehenkari P, et al. Statins and hip fracture prevention--a population based cohort study in women. PLoS One. 2012;7(10): e48095.

[26]Ray WA, Daugherty JR, Griffin MR.Lipid-lowering agents and the risk of hip fracture in a Medicaid population. Inj Prev. 2002; 8(4):276-279.

[27]LaCroix AZ, Cauley JA, Pettinger M, et al. Statin use, clinical fracture, and bone density in postmenopausal women: results from the Women's Health Initiative Observational Study,Ann Intern Med. 2003;139(2):97-104.

[28]Rizzo M, Rini GB. Statins, fracture risk, and bone remodeling: what is true? Am J Med Sci. 2006; 332(2):55-60.

[29]Hatzigeorgiou C, Jackson JL. Hydroxymethylglutaryl- coenzyme A reductase inhibitors and osteoporosis: a meta-analysis. Osteoporos Int. 2005;16(8): 990-998.

[30]Uzzan B, Cohen R, Nicolas P, et al. Effects of statins on bone mineral density: a meta-analysis of clinical studies. Bone. 2007; 40(6):1581-1587.

[31]田发明, 张柳, 孟亚强, 等.辛伐他汀对大鼠骨量及骨髓基质干细胞增殖、分化的影响[J]. 中国骨质疏松杂志, 2007, 13(8): 580-585.

[32]Van Staa TP,Wegman S,de Vres F,et al.Use of statins and risk of fractures. JAMA. 2001;285(14):1850-1855.

[33]Von Stechow D, Fish S, Yahalom D, et al. Does simvastatin stimulate bone formation in vivo？BMC Musculoskelet Disord. 2003; 4: 8.

[34]Ozec I, Kilic E, Gumus C, et al. Effect of local simvastatin application on mandibular defects. J Craniofac Surg. 2007; 18(3):546-550.

[35]Ayukawa Y, Okamura A, Koyano K. Simvastatin promotes osteogenesis around titanium implants. Clin Oral Implants Res. 2004; 15(3):346-350.

[36]Skoglund B, Aspenberg P. Locally applied Simvastatin improves fracture healing in mice.BMC Musculoskelet Disord. 2007; 8:98.

[37]Wang JW, Xu SW, Yang DS, et al. Locally applied simvastatin promotes fracture healing in ovariectomized rat. Osteoporos Int. 2007; 18(12):1641-1650.

[38]Nyan M, Hao J, Miyahara T, et al. Accelerated and Enhanced Bone Formation on Novel Simvastatin-Loaded Porous Titanium Oxide Surfaces. Clin Implant Dent Relat Res. 2013. [Epub ahead of print]

[39]Chou J, Ito T, Bishop D, et al. Controlled Release of Simvastatin from Biomimetic β-TCP Drug Delivery System. PLoS One. 2013; 8(1): e54676.

[40]Qi Y, Zhao T, Yan W, et al. Mesenchymal stem cell sheet transplantation combined with locally released simvastatin enhances bone formation in a rat tibia osteotomy model. Cytotherapy. 2013;15(1):44-56.

[41]Schmitt JM, Hwang K, Winn SR, et al. Bone morphogenetic proteins: an update on basic biology and clinical relevance. J Orthop Res. 1999;17(2):269-278.

[42]Kempen DH, Kruyt MC, Lu L, et al. Effect of autologous bone marrow stromal cell seeding and bone morphogenetic protein-2 delivery on ectopic bone formation in a microsphere/poly(propylene fumarate) composite. Tissue Eng Part A. 2009; 15(3):587-594.

[43]Mbalaviele G, Sheikh S, Stains JP, et al. Beta-catenin and BMP-2 synergize to promote osteoblast differentiation and new bone formation. J Cell Biochem. 2005; 94(2): 403-418.