Skip to main content

Advertisement

SpringerLink
Log in

Comparative impact of systemic delivery of atorvastatin, simvastatin, and lovastatin on bone mineral density of the ovariectomized rats

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Purpose

In addition to lipid-lowering properties, statins have been suggested to affect bone turnover by increasing the osteoblastic bone formation and blocking the osteoclastogenesis. However, there are many controversial reports regarding the beneficial effect of statins on osteoporosis. In this study, we investigated the therapeutic effects of the most important lipophilic statins administered orally for 60 days to the ovariectomized (OVX) female Sprague–Dawley rats and compared the effects on different harvested trabecular and compact bones.

Methods

Thirty female rats were divided into five equal groups including the normal rats, untreated OVX rats (negative control), and the OVX rats treated with atorvastatin (20 mg/kg/day), simvastatin (25 mg/kg/day), and lovastatin (20 mg/kg/day). The osteoporotic animals were treated daily for 60 days and euthanized at the end of experiments. The effectiveness of these treatments was evaluated by biomechanical testing, histopathologic, histomorphometric, micro-CT scan, real-time PCR, and serum biochemical analysis. Moreover, the hepatotoxicity and rhabdomyolysis related with these treatments were assessed by biochemistry analysis and histopathological evaluation.

Results

The results and statistical analysis showed that systemic delivery of simvastatin and lovastatin significantly increased serum calcium level, expression of osteogenic genes, bone mineral density (BMD), and biomechanical properties in comparison to the untreated OVX rats, especially in trabecular bones (P < 0.05). The results of different analysis also indicated that there was no statistical difference between the atorvastatin-treated animals and the negative control. Among all treatments, only atorvastatin showed an evident hepatotoxicity and myopathy.

Conclusions

It was concluded that the lovastatin and simvastatin efficiently ameliorated the OVX-induced osteoporosis. Moreover, the simvastatin-treated animals showed more resemblance to the normal group in terms of BMD, expression of osteogenic genes, serum biochemical parameters, histomorphometric findings, and biomechanical performance with no significant side-effects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. S.L. Bonnick, Osteoporosis in men and women. Clin. Cornerstone 8(1), 28–39 (2006)

    Article  PubMed  Google Scholar 

  2. Z.A. Cole, E.M. Dennison, C. Cooper, Osteoporosis epidemiology update. Curr. Rheumatol. Rep. 10(2), 92–96 (2008)

    Article  PubMed  Google Scholar 

  3. S.B. Jadhav, G.K. Jain, Statins and osteoporosis: new role for old drugs. J. Pharm. Pharmacol. 58(1), 3–18 (2006)

    Article  CAS  PubMed  Google Scholar 

  4. R.A. Adler, Risk factors for osteoporosis 2000–2012. Endocrine 55(3), 664–665 (2017)

    Article  CAS  PubMed  Google Scholar 

  5. G. Mazziotti, J. Bilezikian, E. Canalis, D. Cocchi, A. Giustina, New understanding and treatments for osteoporosis. Endocrine 41(1), 58–69 (2012)

    Article  CAS  PubMed  Google Scholar 

  6. K.A. Kennel, M.T. Drake, Adverse effects of bisphosphonates: implications for osteoporosis management. Mayo Clin. Proc. 84(7), 632–638 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. K.C. An, Selective estrogen receptor modulators. Asian Spine J. 10(4), 787–791 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  8. A. Oryan, A. Kamali, A. Moshiri, Potential mechanisms and applications of statins on osteogenesis: current modalities, conflicts and future directions. J. Control. Release 215, 12–24 (2015)

    Article  CAS  PubMed  Google Scholar 

  9. A. Moshiri, M. Shahrezaee, B. Shekarchi, A. Oryan, K. Azma, Three-dimensional porous gelapin–simvastatin scaffolds promoted bone defect healing in rabbits. Calcif. Tissue Int. 96(6), 552–564 (2015)

    Article  CAS  PubMed  Google Scholar 

  10. A. Moshiri, A.M. Sharifi, A. Oryan, Role of simvastatin on fracture healing and osteoporosis: a systematic review on in vivo investigations. Clin. Exp. Pharmacol. Physiol. 43(7), 659–684 (2016)

    Article  CAS  PubMed  Google Scholar 

  11. A. Oryan, S. Alidadi, A. Moshiri, N. Maffulli, Bone regenerative medicine: classic options, novel strategies, and future directions. J. Orthop. Surg. Res. 9(1), 18 (2014)

    Article  PubMed  PubMed Central  Google Scholar 

  12. A.N. Tsartsalis, C. Dokos, G.D. Kaiafa, D.N. Tsartsalis, A. Kattamis, A.I. Hatzitolios, C.G. Savopoulos, Statins, bone formation and osteoporosis: hope or hype. Hormone 11(2), 126–139 (2012)

    Article  Google Scholar 

  13. J.O. Jansen, J.M. Lord, D.R. Thickett, M.J. Midwinter, D.F. McAuley, F. Gao, Clinical review: statins and trauma–a systematic review. Crit. Care 17(3), 227 (2013)

    Article  PubMed  PubMed Central  Google Scholar 

  14. Z. Du, J. Chen, F. Yan, N. Doan, S. Ivanovski, Y. Xiao, Serum bone formation marker correlation with improved osseointegration in osteoporotic rats treated with simvastatin. Clin. Oral. Implant. Res. 24(4), 422–427 (2013)

    Article  Google Scholar 

  15. I. Gradosova, H. Zivna, K. Svejkovska, V. Palicka, A. Tichy, P. Zivny, The role of atorvastatin in bone metabolism in male albino Wistar rats. Die Pharm. Int. J. Pharm. Sci. 66(8), 606–610 (2011)

    CAS  Google Scholar 

  16. C. Liu, Z. Wu, H. Sun, The effect of simvastatin on mrna expression of transforming growth factor-β1, bone morphogenetic protein-2 and vascular endothelial growth factor in tooth extraction socket. Int. J. Oral. Sci. 1(2), 90–98 (2009)

    Article  PubMed  PubMed Central  Google Scholar 

  17. W. Wang, J.S. Nyman, H.E. Moss, G. Gutierrez, G.R. Mundy, X. Yang, F. Elefteriou, Local low-dose lovastatin delivery improves the bone-healing defect caused by Nf1 loss of function in osteoblasts. J. Bone Mineral. Res. 25(7), 1658–1667 (2010)

    Article  CAS  Google Scholar 

  18. J.P. Issa, C. Ingraci de Lucia, B.G. Dos Santos Kotake, M. Goncalves Gonzaga, F.A. Tocchini de Figueiredo, D. Mizusaki Iyomasa, A.P. Macedo, E. Ervolino, The effect of simvastatin treatment on bone repair of femoral fracture in animal model. Growth Factors 33(2), 139–148 (2015)

    Article  CAS  PubMed  Google Scholar 

  19. Y. Ayukawa, A. Okamura, K. Koyano, Simvastatin promotes osteogenesis around titanium implants. Clin. Oral. Implant. Res. 15(3), 346–350 (2004)

    Article  Google Scholar 

  20. N.I. Ibrahim, M.F. Khamis, M.F.M. Yunoh, S. Abdullah, N. Mohamed, A.N. Shuid, Targeted delivery of lovastatin and tocotrienol to fracture site promotes fracture healing in osteoporosis model: micro-computed tomography and biomechanical evaluation. PloS. One 9(12), e115595 (2014)

    Article  Google Scholar 

  21. S. Chuengsamarn, S. Rattanamongkoulgul, S. Suwanwalaikorn, S. Wattanasirichaigoon, L. Kaufman, Effects of statins vs. non-statin lipid-lowering therapy on bone formation and bone mineral density biomarkers in patients with hyperlipidemia. Bone 46(4), 1011–1015 (2010)

    Article  CAS  PubMed  Google Scholar 

  22. T. Majima, Y. Komatsu, A. Fukao, K. Ninomiya, T. Matsumura, K. Nakao, Short-term effects of atorvastatin on bone turnover in male patients with hypercholesterolemia. Endocr. J. 54(1), 145–151 (2007)

    Article  CAS  PubMed  Google Scholar 

  23. B. Chang, J. Yang, H. Li, S. Lu, L. Chen, P. Fang, Effects of atorvastatin on bone metabolism and bone mineral density in Wistar rats. Die Pharm. 66(7), 535–537 (2011)

    CAS  Google Scholar 

  24. K. Esposito, A. Capuano, L. Sportiello, A. Giustina, D. Giugliano, Should we abandon statins in the prevention of bone fractures? Endocrine 44(2), 326–333 (2013)

    Article  CAS  PubMed  Google Scholar 

  25. F.J. Maritz, M.M. Conradie, P.A. Hulley, R. Gopal, S. Hough, Effect of statins on bone mineral density and bone histomorphometry in rodents. Arterioscler. Thromb. Vasc. Biol. 21(10), 1636–1641 (2001)

    Article  CAS  PubMed  Google Scholar 

  26. S.B. Jadhav, P.S. Narayana Murthy, M.M. Singh, G.K. Jain, Distribution of lovastatin to bone and its effect on bone turnover in rats. J. Pharm. Pharmacol. 58(11), 1451–1458 (2006)

    Article  CAS  PubMed  Google Scholar 

  27. R. Ogasawara, Y. Furuya, H. Sasaki, M. Yoshinari, Y. Yajima, Effects of oral administration of simvastatin on bone formation in senile osteoporosis rat. J. Hard Tissue Biol. 22(4), 461–472 (2013)

    Article  Google Scholar 

  28. M. Thapar, M.W. Russo, H.L. Bonkovsky, Statins and Liver Injury. Gastroenterol. Hepatol. 9(9), 605–606 (2013)

    Google Scholar 

  29. J. Sidaway, Y. Wang, A.M. Marsden, T.C. Orton, F.R. Westwood, C.T. Azuma, R.C. Scott, Statin-induced myopathy in the rat: relationship between systemic exposure, muscle exposure and myopathy. Xenobiotica 39(1), 90–98 (2009)

    Article  CAS  PubMed  Google Scholar 

  30. V. Alt, U. Thormann, S. Ray, D. Zahner, L. Dürselen, K. Lips, T. El Khassawna, C. Heiss, A. Riedrich, G. Schlewitz, A. Ignatius, M. Kampschulte, H. von Dewitz, S. Heinemann, R. Schnettler, A. Langheinrich, A new metaphyseal bone defect model in osteoporotic rats to study biomaterials for the enhancement of bone healing in osteoporotic fractures. Acta Biomater. 9(6), 7035–7042 (2013)

    Article  CAS  PubMed  Google Scholar 

  31. X. Xu, H. Chen, X. Zhang, Z. Zhai, X. Liu, A. Qin, E. Lu, Simvastatin prevents alveolar bone loss in an experimental rat model of periodontitis after ovariectomy. J. Transl. Med. 12, 284 (2014) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192445/

  32. N. El-Nabarawi, M. El-Wakd, M. Salem, Atorvastatin, a double weapon in osteoporosis treatment: an experimental and clinical study. Drug. Des. Dev. Ther. 11, 1383–1391 (2017)

    Article  Google Scholar 

  33. A. Oryan, A. Bigham-Sadegh, F. Abbasi-Teshnizi, Effects of osteogenic medium on healing of the experimental critical bone defect in a rabbit model. Bone 63, 53–60 (2014)

    Article  CAS  PubMed  Google Scholar 

  34. M. Yamauchi, T. Yamaguchi, K. Nawata, K.-i Tanaka, S. Takaoka, T. Sugimoto, Increased low-density lipoprotein cholesterol level is associated with non-vertebral fractures in postmenopausal women. Endocrine 48(1), 279–286 (2015)

    Article  CAS  PubMed  Google Scholar 

  35. Z. Wang, Y. Li, F. Zhou, Z. Piao, J. Hao, Effects of statins on bone mineral density and fracture risk: A Prisma-compliant systematic review and meta-analysis. Medicine 95(22), e3042 (2016) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900696/

  36. Y.P. Kharode, M.C. Sharp, P.V. Bodine, Utility of the ovariectomized rat as a model for human osteoporosis in drug discovery. Osteoporosisc 455, 111–124 (2008)

    Article  CAS  Google Scholar 

  37. M.M. Elkomy, F.G. Elsaid, Anti-osteoporotic effect of medical herbs and calcium supplementation on ovariectomized rats. J. Basic Appl. Zool. 72(Supplement C), 81–88 (2015)

    Article  CAS  Google Scholar 

  38. P.P. Lelovas, T.T. Xanthos, S.E. Thoma, G.P. Lyritis, I.A. Dontas, The laboratory rat as an animal model for osteoporosis research. Comp. Med. 58(5), 424–430 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  39. S.R. Shah, C.A. Werlang, F.K. Kasper, A.G. Mikos, Novel applications of statins for bone regeneration. Natl. Sci. Rev. 2(1), 85–99 (2015)

    Article  PubMed  Google Scholar 

  40. J.B. Park, The use of simvastatin in bone regeneration. Med. Oral. Patol. Oral. Cir. Bucal 14(9), e485–e488 (2009)

    PubMed  Google Scholar 

  41. T. Kawane, S. Terashima, I. Kurahashi, T. Yanagawa, H. Yoshida, N. Horiuchi, Atorvastatin enhances bone density in ovariectomized rats given 17β-estradiol or human parathyroid hormone (1–34). Endocrine 24(2), 121–129 (2004)

    Article  CAS  PubMed  Google Scholar 

  42. H.G. Bone, D.P. Kiel, R.S. Lindsay, E.M. Lewiecki, M.A. Bolognese, E.T. Leary, W. Lowe, M.R. McClung, Effects of atorvastatin on bone in postmenopausal women with dyslipidemia: a double-blind, placebo-controlled, dose-ranging trial. J. Clin. Endocrinol. Metab. 92(12), 4671–4677 (2007)

    Article  CAS  PubMed  Google Scholar 

  43. Y. Uyar, Y. Baytur, U. Inceboz, B.C. Demir, G. Gumuser, K. Ozbilgin, Comparative effects of risedronate, atorvastatin, estrogen and SERMs on bone mass and strength in ovariectomized rats. Maturitas 63(3), 261–267 (2009)

    Article  CAS  PubMed  Google Scholar 

  44. S. Lin, J. Huang, Z. Fu, Y. Liang, H. Wu, L. Xu, Y. Sun, W.Y. Lee, T. Wu, L. Qin, The effects of atorvastatin on the prevention of osteoporosis and dyslipidemia in the high-fat-fed ovariectomized rats. Calcif. Tissue Int. 96(6), 541–551 (2015)

    Article  CAS  PubMed  Google Scholar 

  45. I. Gradosova, H. Zivna, V. Palicka, S. Hubena, K. Svejkovska, P. Zivny, Protective effect of atorvastatin on bone tissue in orchidectomised male albino Wistar rats. Eur. J. Pharmacol. 679(1-3), 144–150 (2012)

    Article  CAS  PubMed  Google Scholar 

  46. S. Abdul-Majeed, N. Mohamed, I.-N. Soelaiman, Effects of tocotrienol and lovastatin combination on osteoblast and osteoclast activity in estrogen-deficient osteoporosis. Evidence-Based Complementary and Alternative Medicine 2012, ID 960742 (2012) https://www.hindawi.com/journals/ecam/2012/960742/

  47. T. An, J. Hao, S. Sun, R. Li, M. Yang, G. Cheng, M. Zou, Efficacy of statins for osteoporosis: a systematic review and meta-analysis. Osteoporos. Int. 28(1), 47–57 (2017)

    Article  CAS  PubMed  Google Scholar 

  48. L.J. Qiao, K.L. Kang, J.S. Heo, Simvastatin promotes osteogenic differentiation of mouse embryonic stem cells via canonical Wnt/β-catenin signaling. Mol. Cells 32(5), 437–444 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. J. Pagkalos, J.M. Cha, Y. Kang, M. Heliotis, E. Tsiridis, A. Mantalaris, Simvastatin induces osteogenic differentiation of murine embryonic stem cells. J. Bone Mineral. Res. 25(11), 2470–2478 (2010)

    Article  CAS  Google Scholar 

  50. J. Jose, F.A.A. Al-Tamimi, M.M. Helal, B. Jimmy, Q. Al Riyami, Statin associated associated hepatic adverse effects: a retrospective review from a regional hospital in sultanate of oman. Oman Med. J. 29(5), 351–357 (2014)

    Article  PubMed  PubMed Central  Google Scholar 

  51. A.T. Clarke, P.C. Johnson, G.C. Hall, I. Ford, P.R. Mills, High dose atorvastatin associated with increased risk of significant hepatotoxicity in comparison to simvastatin in UK GPRD cohort. PLoS. One 11(3), e0151587 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  52. S.O. El-Ganainy, A. El-Mallah, D. Abdallah, M.M. Khattab, M.M. Mohy El-Din, A.S. El-Khatib, Elucidation of the mechanism of atorvastatin-induced myopathy in a rat model. Toxicology 359–360(Supplement C), 29–38 (2016)

    Article  PubMed  Google Scholar 

  53. K. Mukaiyama, M. Kamimura, S. Uchiyama, S. Ikegami, Y. Nakamura, H. Kato, Elevation of serum alkaline phosphatase (ALP) level in postmenopausal women is caused by high bone turnover. Aging Clin. Exp. Res. 27(4), 413–418 (2015)

    Article  PubMed  Google Scholar 

  54. H.A. Fink, S. Litwack-Harrison, B.C. Taylor, D.C. Bauer, E.S. Orwoll, C.G. Lee, E. Barrett-Connor, J.T. Schousboe, D.M. Kado, P.S. Garimella, K.E. Ensrud, Clinical utility of routine laboratory testing to identify possible secondary causes in older men with osteoporosis: the Osteoporotic Fractures in Men (MrOS) Study. Osteoporos. Int. 27(1), 331–338 (2016)

    Article  CAS  PubMed  Google Scholar 

  55. A. Panico, G.A. Lupoli, F. Marciello, R. Lupoli, M. Cacciapuoti, A. Martinelli, L. Granieri, D. Iacono, G. Lupoli, Teriparatide vs. alendronate as a treatment for osteoporosis: changes in biochemical markers of bone turnover, BMD and quality of life. Med. Sci. Monit. 17(8), Cr442–Cr448 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. A. Egan, E. Colman, Weighing the benefits of high-dose simvastatin against the risk of myopathy. New Engl. J. Med. 365(4), 285–287 (2011)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Dr. Ali Moshiri for sharing his pearls of wisdom with us during the course of this research.

Author information

Authors and Affiliations

  1. Department of Orthopedic Surgery, School of Medicine, AJA University of Medical Science, Tehran, Iran

    Mostafa Shahrezaee & Amir Kamali

  2. Department of Pathology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran

    Ahmad Oryan

  3. Dental Research Center, Research Institute of Dental Sciences, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Farshid Bastami & Sepanta Hosseinpour

  4. School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Farshid Bastami

  5. School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran

    Mohammad Hossein Shahrezaee

Authors
  1. Mostafa Shahrezaee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ahmad Oryan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Farshid Bastami
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sepanta Hosseinpour
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mohammad Hossein Shahrezaee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Amir Kamali
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amir Kamali.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shahrezaee, M., Oryan, A., Bastami, F. et al. Comparative impact of systemic delivery of atorvastatin, simvastatin, and lovastatin on bone mineral density of the ovariectomized rats. Endocrine 60, 138–150 (2018). https://doi.org/10.1007/s12020-018-1531-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-018-1531-6

Keywords

Search

Navigation