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Local injection of a single dose of simvastatin augments osteoporotic bone mass in ovariectomized rats

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Abstract

The aim of this study was to evaluate the effects and explore the mechanism of a local injection of a single dose of simvastatin as a strategy to strengthen target bone. Simvastatin was injected into the femurs (5 or 10 mg) or caudal vertebrae (1 or 2 mg) of ovariectomized rats, with an equal volume of vehicle injected as a control. Bone mineral density (BMD), bone microstructure and strength were evaluated at 1 and 5 months post-injection for the femurs and at 12 days post-injection for the vertebrae. Bone mass, adipocyte numbers and Runx2 expression were also examined using histology and immunohistochemistry. Compared with controls, simvastatin significantly increased BMD, bone volume fraction (BV/TV), improved bone microstructural parameters and bone strength in the femurs at both time points (all P < 0.01). Simvastatin-treated femurs contained fewer adipocytes and a higher Runx2 expression. For the caudal vertebrae, simvastatin significantly improved BV/TV, bone microstructures, and bone strength (all P < 0.01) as compared with controls. In conclusion, local injection of a single dose of simvastatin induces early onset and long-lasting bone augmentation in osteoporotic bone, significantly improving BMD, and bone microstructure and biomechanical strength. Simvastatin induces Runx2 expression, which may function to induce osteogenesis and inhibit adipogenesis as an underlying mechanism to augment bone mass.

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References

  1. Van Staa TP, Leufkens HG, Cooper C (2002) Does a fracture at one site predict later fractures at other sites? A British cohort study. Osteoporos Int 13:624–629

    Article  PubMed  Google Scholar 

  2. Curran D, Maravic M, Kiefer P, Tochon V, Fardellone P (2010) Epidemiology of osteoporosis-related fractures in France: a literature review. Joint Bone Spine 77:546–551

    Article  PubMed  Google Scholar 

  3. Melton LJ 3rd, Chrischilles EA, Cooper C, Lane AW, Riggs BL (1992) Perspective. How many women have osteoporosis? J Bone Miner Res 7:1005–1010

    Article  PubMed  Google Scholar 

  4. Jones G, Nguyen T, Sambrook PN, Kelly PJ, Gilbert C, Eisman JA (1994) Symptomatic fracture incidence in elderly men and women: the Dubbo Osteoporosis Epidemiology Study (DOES). Osteoporos Int 4:277–282

    Article  CAS  PubMed  Google Scholar 

  5. Van Balen R, Steyerberg EW, Polder JJ, Ribbers TL, Habbema JD, Cools HJ (2001) Hip fracture in elderly patients: outcomes for function, quality of life, and type of residence. Clin Orthop Relat Res 390:232–243

    Article  PubMed  Google Scholar 

  6. Greenspan SL, Beck TJ, Resnick NM, Bhattacharya R, Parker RA (2005) Effect of hormone replacement, alendronate, or combination therapy on hip structural geometry: a 3-year, double-blind, placebo-controlled clinical trial. J Bone Miner Res 20:1525–1532

    Article  CAS  PubMed  Google Scholar 

  7. Gallagher AM, Rietbrock S, Olson M, van Staa TP (2008) Fracture outcomes related to persistence and compliance with oral bisphosphonates. J Bone Miner Res 23:1569–1575

    Article  PubMed  Google Scholar 

  8. Cramer JA, Gold DT, Silverman SL, Lewiecki EM (2007) A systematic review of persistence and compliance with bisphosphonates for osteoporosis. Osteoporos Int 18:1023–1031

    Article  CAS  PubMed  Google Scholar 

  9. Barlow DH (2007) Osteoporosis guidelines. Climacteric Suppl 2:79–82

    Article  Google Scholar 

  10. Verron E, Gauthier O, Janvier P, Pilet P, Lesoeur J, Bujoli B, Guicheux J, Bouler JM (2010) In vivo bone augmentation in an osteoporotic environment using bisphosphonate-loaded calcium deficient apatite. Biomaterials 31:7776–7784

    Article  CAS  PubMed  Google Scholar 

  11. Wu ZX, Liu D, Wan SY, Cui G, Zhang Y, Lei W (2011) Sustained-release rhBMP-2 increased bone mass and bone strength in an ovine model of postmenopausal osteoporosis. J Orthop Sci 16:99–104

    Article  CAS  PubMed  Google Scholar 

  12. Phillips FM, Turner AS, Seim HB 3rd, MacLeay J, Toth CA, Pierce AR, Wheeler DL (2006) In vivo BMP-7 (OP-1) enhancement of osteoporotic vertebral bodies in an ovine model. Spine J 6:500–506

    Article  PubMed  Google Scholar 

  13. Mundy G, Garrett R, Harris S, Chan J, Chen D, Rossini G, Boyce B, Zhao M, Gutierrez G (1999) Stimulation of bone formation in vitro and in rodents by statins. Science 286:1946–1949

    Article  CAS  PubMed  Google Scholar 

  14. Song C, Guo Z, Ma Q, Chen Z, Liu Z, Jia H, Dang G (2003) Simvastatin induces osteoblastic differentiation and inhibits adipocytic differentiation in mouse bone marrow stromal cells. Biochem Biophys Res Commun 308:458–462

    Article  CAS  PubMed  Google Scholar 

  15. Li X, Song QS, Wang JY, Leng HJ, Chen ZQ, Liu ZJ, Dang GT, Song CL (2011) Simvastatin induces estrogen receptor-alpha expression in bone, restores bone loss, and decreases ERα expression and uterine wet weight in ovariectomized rats. J Bone Miner Metab 29:396–403

    Article  CAS  PubMed  Google Scholar 

  16. Reid IR, Hague W, Emberson J, Baker J, Tonkin A, Hunt D, MacMahon S, Sharpe N (2001) Effect of pravastatin on frequency of fracture in the LIPID study: secondary analysis of a randomised controlled trial. Long-term intervention with pravastatin in ischaemic disease. Lancet 357:509–512

    Article  CAS  PubMed  Google Scholar 

  17. Patil S, Holt G, Raby N, McLellan AR, Smith K, O’Kane S, Beastall G, Crossan JF (2009) Prospective, double blind, randomized, controlled trial of simvastatin in human fracture healing. J Orthop Res 27:281–285

    Article  CAS  PubMed  Google Scholar 

  18. Schachter M (2005) Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol 19:117–125

    Article  CAS  PubMed  Google Scholar 

  19. Wang JW, Xu SW, Yang DS, Lv RK (2007) Locally applied simvastatin promotes fracture healing in ovariectomized rat. Osteoporos Int 18:1641–1650

    Article  PubMed  Google Scholar 

  20. Wang ML, Massie J, Perry A, Garfin SR, Kim CW (2007) A rat osteoporotic spine model for the evaluation of bioresorbable bone cements. Spine J 7:466–474

    Article  PubMed  Google Scholar 

  21. Tsujio M, Mizorogi T, Kitamura I, Maeda Y, Nishijima K, Kuwahara S, Ohno T, Niida S, Nagaya M, Saito R, Tanaka S (2009) Bone mineral analysis through dual energy X-ray absorptiometry in laboratory animals. J Vet Med Sci 71:1493–1497

    Article  PubMed  Google Scholar 

  22. Gittens SA, Wohl GR, Zernicke RF, Matyas JR, Morley P, Uludag H (2004) Systemic bone formation with weekly PTH administration in ovariectomized rats. J Pharm Pharm Sci 7:27–37

    CAS  PubMed  Google Scholar 

  23. Brouwers JE, Ruchelsman M, Rietbergen B, Bouxsein ML (2009) Determination of rat vertebral bone compressive fatigue properties in untreated intact rats and zoledronic-acid-treated, ovariectomized rats. Osteoporos Int 20:1377–1384

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Stürmer EK, Seidlová-Wuttke D, Sehmisch S, Rack T, Wille J, Frosch KH, Wuttke W, Stürmer KM (2006) Standardized bending and breaking test for the normal and osteoporotic metaphyseal tibias of the rat: effect of estradiol, testosterone, and raloxifene. J Bone Miner Res 21:89–96

    Article  PubMed  Google Scholar 

  25. Søgaard CH, Wronski TJ, McOsker JE, Mosekilde L (1994) The positive effect of parathyroid hormone on femoral neck bone strength in ovariectomized rats is more pronounced than that of estrogen or bisphosphonates. Endocrinology 134:650–657

    PubMed  Google Scholar 

  26. Ke HZ, Shen VW, Qi H, Crawford DT, Wu DD, Liang XG, Chidsey-Frink KL, Pirie CM, Simmons HA, Thompson DD (1998) Prostaglandin E2 increases bone strength in intact rats and in ovariectomized rats with established osteopenia. Bone 23:249–255

    Article  CAS  PubMed  Google Scholar 

  27. Tamura N, Kurabayashi T, Nagata H, Matsushita H, Yahata T, Tanaka K (2005) Effects of testosterone on cancellous bone, marrow adipocytes, and ovarian phenotype in a young female rat model of polycystic ovary syndrome. Fertil Steril S2:1277–1284

    Article  Google Scholar 

  28. Feng X, McDonald JM (2011) Disorders of bone remodeling. Annu Rev Pathol 6:121–145

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Félix Lanao RP, Leeuwenburgh SC, Wolke JG, Jansen JA (2011) In vitro degradation rate of apatitic calcium phosphate cement with incorporated PLGA microspheres. Acta Biomater 7:3459–3468

    Article  PubMed  Google Scholar 

  30. Jämsä T, Tuukkanen J, Jalovaara P (1998) Femoral neck strength of mouse in two loading configurations: method evaluation and fracture characteristics. J Biomech 31:723–729

    Article  PubMed  Google Scholar 

  31. Zhang G, Qin L, Shi Y, Leung K (2005) A comparative study between axial compression and lateral fall configuration tested in a rat proximal femur model. Clin Biomech (Bristol, Avon) 20:729–735

    Article  Google Scholar 

  32. Miyakoshi N, Sato K, Abe T, Tsuchida T, Tamura Y, Kudo T (1999) Histomorphometric evaluation of the effects of ovariectomy on bone turnover in rat caudal vertebrae. Calcif Tissue Int 64:318–324

    Article  CAS  PubMed  Google Scholar 

  33. Wronski TJ, Dann LM, Horner SL (1989) Time course of vertebral osteopenia in ovariectomized rats. Bone 10:295–301

    Article  CAS  PubMed  Google Scholar 

  34. Westerlind KC, Wronski TJ, Ritman EL, Luo ZP, An KN, Bell NH, Turner RT (1997) Estrogen regulates the rate of bone turnover but bone balance in ovariectomized rats is modulated by prevailing mechanical strain. Proc Natl Acad Sci USA 94:4199–4204

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Syed FA, Oursler MJ, Hefferanm TE, Peterson JM, Riggs BL, Khosla S (2008) Effects of estrogen therapy on bone marrow adipocytes in postmenopausal osteoporotic women. Osteoporos Int 19:1323–1330

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Li Y, Li J, Zhu S, Luo E, Feng G, Chen Q, Hu J (2012) Effects of strontium on proliferation and differentiation of rat bone marrow mesenchymal stem cells. Biochem Biophys Res Commun 418:725–730

    Article  CAS  PubMed  Google Scholar 

  37. Gimble JM, Nuttall ME (2012) The relationship between adipose tissue and bone metabolism. Clin Biochem 45:874–879

    Article  CAS  PubMed  Google Scholar 

  38. Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, Rosewell IR, Stamp GW, Beddington RS, Mundlos S, Olsen BR, Selby PB, Owen MJ (1997) Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89(5):765–771

    Article  CAS  PubMed  Google Scholar 

  39. Rutten S, Nolte PA, Korstjens CM, Klein-Nulend J (2009) Low-intensity pulsed ultrasound affects RUNX2 immunopositive osteogenic cells in delayed clinical fracture healing. Bone 45(5):862–869

    Article  CAS  PubMed  Google Scholar 

  40. Marie PJ (2008) Transcription factors controlling osteoblastogenesis. Arch Biochem Biophys 473:98–105

    Article  CAS  PubMed  Google Scholar 

  41. Fowlkes JL, Bunn RC, Liu L, Wahl EC, Coleman HN, Cockrell GE, Perrien DS, Lumpkin CK Jr, Thrailkill KM (2008) Runt-related transcription factor 2 (RUNX2) and RUNX2-related osteogenic genes are down-regulated throughout osteogenesis in type 1 diabetes mellitus. Endocrinology 149:1697–1704

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Cheung WM, Ng WW, Kung AW (2006) Dimethyl sulfoxide as an inducer of differentiation in preosteoblast MC3T3-E1 cells. FEBS Lett 580:121–126

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by Grants from the National Natural Science Foundation of China (Project Nos. 81171693, 81100895, 11002004) and the Program for New Century Excellent Talents in University (Project No. NCET-10-0202).

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Authors and Affiliations

  1. Department of Orthopedics, Peking University Third Hospital, Bei**g, 100191, China

    Ning Yang, Yueyi Cui, Jie Tan, **n Fu, **aoguang Han & Chunli Song

  2. Bei**g Key Laboratory of Spinal Diseases, Bei**g, 100191, China

    Huijie Leng & Chunli Song

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  1. Ning Yang
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  2. Yueyi Cui
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  3. Jie Tan
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Correspondence to Chunli Song.

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Yang, N., Cui, Y., Tan, J. et al. Local injection of a single dose of simvastatin augments osteoporotic bone mass in ovariectomized rats. J Bone Miner Metab 32, 252–260 (2014). https://doi.org/10.1007/s00774-013-0496-z

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  • DOI: https://doi.org/10.1007/s00774-013-0496-z

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