Skip to main content
SpringerLink
Log in

The Effects of Atorvastatin on the Prevention of Osteoporosis and Dyslipidemia in the High-Fat-Fed Ovariectomized Rats

  • Original Research
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

Previous studies reported that statins showed positive effects on bone in both human and animal models. This study aimed to investigate the effects of atorvastatin on the prevention of osteoporosis and dyslipidemia in ovariectomized rats fed with high-fat emulsion. The 3-month-old female rats were subjected to either sham operations (n = 8) or ovariectomized operations (OVX, n = 24). The OVX rats were orally administered deionized water (n = 8) or standardized high-fat emulsion without (n = 8) or with atorvastatin (n = 8). All rats were injected twice with calcein before sacrificed for the purpose of double in vivo labeling. After 12 weeks, all rats were sacrificed under anesthesia. Biochemistry, histomorphometry, mechanical test, micro-computed tomography analysis, mechanical test, histology, and component analysis were performed. We found that high-fat emulsion significantly decreased body weight, bone formation, collagen content of bone, and bone biomechanics, while increased blood, liver, and bone marrow lipids. Atorvastatin treatment prevented dyslipidemia, reversed hepatic steatosis, optimized composition of bone, and improved bone mechanical properties. The current study provided further evidence that atorvastatin might be useful for the treatment of osteoporotic patients with dyslipidemia.

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
Fig. 6

Similar content being viewed by others

References

  1. Xia WB, He SL, Xu L, Liu AM, Jiang Y, Li M, Wang O, Xing XP, Sun Y, Cummings SR (2012) Rapidly increasing rates of hip fracture in Beijing, China. J Bone Miner Res 27:125–129

    Article  PubMed  Google Scholar 

  2. Cooper C, Cole ZA, Holroyd CR, Earl SC, Harvey NC, Dennison DM, Melton LJ, Cummings SR, Kanis JA (2011) Secular trends in the incidence of hip and other osteoporotic fractures. Osteoporos Int 22:1277–1288

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Wohl GR, Loehrke L, Watkins BA, Zernicke RF (1998) Effects of high-fat diet on mature bone mineral content, structure, and mechanical properties. Calcif Tissue Int 63:74–79

    Article  CAS  PubMed  Google Scholar 

  4. van Beek E, Pieterman E, Cohen L, Lowik C, Papapoulos S (1999) Farnesyl pyrophosphate synthase is the molecular target of nitrogen-containing bisphosphonates. Biochem Biophys Res Commun 264:108–111

    Article  PubMed  Google Scholar 

  5. Fisher JE, Rogers MJ, Halasy JM, Luckman SP, Hughes DE, Masarachia PJ, Wesolowski G, Russell RG, Rodan GA, Reszka AA (1999) Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci USA 96:133–138

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Halcox JP, Deanfield JE (2004) Beyond the laboratory: clinical implications for statin pleiotropy. Circulation 109:II42–II48

    Article  PubMed  Google Scholar 

  7. Maritz FJ, Conradie MM, Hulley PA, Gopal R, Hough S (2001) Effect of statins on bone mineral density and bone histomorphometry in rodents. Arterioscler Thromb Vasc Biol 21:1636–1641

    Article  CAS  PubMed  Google Scholar 

  8. Drake Matthew T, Clarke Bart L, Khosla Sundeep (2008) Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc 83:1032–1045

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Grasser WA, Baumann AP, Petras SF, Harwood HJ Jr, Devalaraja R, Renkiewicz R, Baragi V, Thompson DD, Paraklar VM (2003) Regulation of osteoclast differentiation by statins. J Musculoskelet Neuronal Interact 3:53–62

    CAS  PubMed  Google Scholar 

  10. Chen PY, Sun JS, Tsuang YH, Chen MH, Weng PW, Lin FH (2010) Simvastatin promotes osteoblast viability and differentiation via Ras/Smad/Erk/BMP-2 signaling pathway. Nutr Resm 30:191–199

    Article  CAS  Google Scholar 

  11. Maeda T, Matsunuma A, Kawane T, Horiuchi N (2001) Simvastatin promotes osteoblast differentiation and mineralization in MC3T3-E1 cells. Biochem Biophys Res Commun 280:874–877

    Article  CAS  PubMed  Google Scholar 

  12. Chan KA, Andrade SE, Boles M, Buist DS, Chase GA, Donahue JG, Goodman MJ, Gurwitz JH, LaCroix AZ, Platt R (2000) Inhibitors of hydroxymethylglutaryl-coenzyme A reductase and risk of fracture among older women. Lancet 355:2185–2188

    Article  CAS  PubMed  Google Scholar 

  13. Uysal AR, Delibasi T, Erdogan MF, Kamel N, Baskal N, Tonyukuk V, Corapcioglu D, Güllü S, Erdogan G (2007) Effect of simvastatin use on bone mineral density in women with type 2 diabetes. Endocr Pract 13:114–116

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. Majima T, Shimatsu A, Komatsu Y, Satoh N, Fukao A, Ninomiya K, Matsumura T, Nakao K (2007) Shortterm effects of pitavastatin on biochemical markers of bone turnover in patients with hypercholesterolemia. Intern Med 46:1967–1973

    Article  PubMed  Google Scholar 

  16. Safaei H, Janghorbani M, Aminorroaya A, Amini M (2007) Lovastatin effects on bone mineral density in postmenopausal women with type 2 diabetes mellitus. Acta Diabetol 44:76–82

    Article  CAS  PubMed  Google Scholar 

  17. Schoofs MW, Sturkenboom MC, van der Klift M, Hofman A, Pols HA, Stricker BH (2004) HMG-CoA reductase inhibitors and the risk of vertebral fracture. J Bone Miner Res 19:1525–1530

    Article  CAS  PubMed  Google Scholar 

  18. Rejnmark L, Olsen ML, Johnsen SP, Vestergaard P, Sorensen HT, Mosekildeb L (2004) Hip fracture risk in statin users: a population-based Danish case-control study. Osteoporos Int 15:452–458

    PubMed  Google Scholar 

  19. Hatzigeorgiou C, Jackson JL (2005) Hydroxymethylglutaryl-coenzyme A reductase inhibitors and osteoporosis: a meta-analysis. Osteoporos Int 16:990–998

    Article  CAS  PubMed  Google Scholar 

  20. Uzzan B, Cohen R, Nicolas P, Cucherat M, Perret GY (2007) Effects of statins on bone mineral density: a meta-analysis of clinical studies. Bone 40:1581–1587

    Article  CAS  PubMed  Google Scholar 

  21. Bone HG, Kiel DP, Lindsay RS, Lewiecki EM, Bolognese MA, Leary ET, Lowe W, McClung MR (2007) Effects of atorvastatin on bone in postmenopausal women with dyslipidemia: a double-blind, placebo-controlled, dose-ranging trial. J Clin Endocrinol Metab 92:4671–4677

    Article  CAS  PubMed  Google Scholar 

  22. Huang JH, Huang XH, Chen ZY, Zheng QS, Sun RY (2004) Dose conversion among different animals and healthy volunteers in pharmacological study. Chin J Clin Pharmacol Ther 9:1069–1072

    Google Scholar 

  23. U.S. Food and Drug Administration (2005) FDA Guidance for industry and reviews estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. Available from: http://www.fda.gov/downloads/Drugs/Guidances/UCM078932.pdf Accessed 07 May 2005

  24. Lin SE, Huang JP, Wu LZ, Wu T, Cui L (2013) Prevention of osteopenia and dyslipidemia in rats after ovariectomy with combined aspirin and low-dose diethylstilbestrol. Biomed Environ Sci 26:249–257

    CAS  PubMed  Google Scholar 

  25. Cui L, Li T, Liu Y, Li P, Xu B, Huang L, Chen Y, Liu Y, Tian X, Jee WS, Wu T (2012) Salvianolic acid B prevents bone loss in prednisone-treated rats through stimulation of osteogenesis and bone marrow angiogenesis. PLoS One 7:e34647

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Lin SE, Huang JP, Zheng L, Liu YZ, Liu GH, Li N, Wang KX, Zou LY, Wu T, Qin L, Cui L, Li G (2014) Glucocorticoid-induced osteoporosis in growing rats. Calcif Tissue Int 95:362–373

    Article  CAS  PubMed  Google Scholar 

  27. Dempster DW, Compston JE, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR, Parfitt AM (2013) Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 28:2–17

    Article  PubMed Central  PubMed  Google Scholar 

  28. Campbell GM, Bernhardt R, Scharnweber D, Boyd SK (2011) The bone architecture is enhanced with combined PTH and alendronate treatment compared to monotherapy while maintaining the state of surface mineralization in the OVX rat. Bone 49:225–232

    Article  CAS  PubMed  Google Scholar 

  29. Mahanti HS, Barnes RM (1983) Determination of major, minor and trace elements in bone by inductively-coupled plasma emission spectrometry. Anal Chim Acta 151:409–417

    Article  CAS  Google Scholar 

  30. Little Tanya J, Feinle-Bisset Christine (2010) Oral and gastrointestinal sensing of dietary fat and appetite regulation in humans: modification by diet and obesity. Front Neurosci 4:178

    PubMed Central  PubMed  Google Scholar 

  31. Paquette A, Shinoda M, Rabasa Lhoret R, Prud’homme D, Lavoie JM (2007) Time course of liver lipid infiltration in ovariectomized rats: impact of a high-fat diet. Maturitas 58:182–190

    Article  CAS  PubMed  Google Scholar 

  32. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ (2004) Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 110:227–239

    Article  PubMed  Google Scholar 

  33. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (2001) Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 285:2486–2497

    Article  Google Scholar 

  34. Stein EA (2003) The power of statins: aggressive lipid lowering. Clin Cardiol 26:III25–III31

    Article  PubMed  Google Scholar 

  35. Parhami F, Tintut Y, Beamer WG, Gharavi N, Goodman W, Demer LL (2001) Atherogenic high-fat diet reduces bone mineralization in mice. J Bone Miner Res 16:182–188

    Article  CAS  PubMed  Google Scholar 

  36. Cao JJ, Gregoire BR, Gao H (2009) High-fat diet decreases cancellous bone mass but has no effect on cortical bone mass in the tibia in mice. Bone 44:1097–1104

    Article  CAS  PubMed  Google Scholar 

  37. Patsch JM, Kiefer FW, Varga P, Pail P, Rauner M, Stupphann D, Resch H, Moser D, Zysset PK, Stulnig TM, Pietschmann P (2011) Increased bone resorption and impaired bone microarchitecture in short-term and extended high-fat diet-induced obesity. Metabolism 60:243–249

    Article  CAS  PubMed  Google Scholar 

  38. Seeman E, Delmas PD (2006) Bone quality–the material and structural basis of bone strength and fragility. N Engl J Med 354:2250–2261

    Article  CAS  PubMed  Google Scholar 

  39. Kaji H, Kanatani M, Sugimoto T, Chihara K (2005) Statins modulate the levels of osteoprotegerin/receptor activator of NFκB ligand mRNA in mouse bonecell cultures. Horm Metab Res 37:589–592

    Article  CAS  PubMed  Google Scholar 

  40. Viereck V, Grundker C, Blaschke S, Frosch KH, Schoppet M, Emons G, Hofbauer LC (2005) Atorvastatin stimulates the production of osteoprotegerin by human osteoblasts. J Cell Biochem 96:1244–1253

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This project was funded by Science & Technology Innovation Fund of Guangdong Medical College (No STIF201104) and Science and Technology Planning Project of Zhanjiang (No 2012C3102015). The works were also supported in part by SMART program, Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong. We wish to thank Dr. David William Green at the University of Hong Kong for his contribution on English language editing and grammar correction of the manuscript.

Conflict of Interest

Sien Lin, Jianping Huang, Ziwei Fu,Yanlong Liang, Haiyou Wu, Liangliang Xu, Yuxin Sun, Wayne YW Lee, Tie Wu, Ling Qin, Liao Cui, and Gang Li declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

All animal experiments were approved by the Academic Committee on the Ethics of Animal Experiments of the Guangdong Medical College, Zhanjiang, China. Permit Number: SYXK (GUANGDONG) 2008-0007. All procedures performed in studies involving animals were in accordance with the ethical standards of Guangdong Medical College.

Author information

Author notes

    Authors and Affiliations

    1. Department of Pharmacology, Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical College, Zhanjiang, 524023, Guangdong, China

      Sien Lin, Ziwei Fu, Yanlong Liang, Haiyou Wu, Tie Wu & Liao Cui

    2. Department of Orthopaedics and Traumatology and Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, SAR, China

      Sien Lin, Liangliang Xu, Yuxin Sun, Wayne Y. W. Lee, Ling Qin & Gang Li

    3. The CUHK-ACC Space Medicine Centre on Health Maintenance of Musculoskeletal System, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Guangdong, China

      Sien Lin, Wayne Y. W. Lee & Gang Li

    4. Department of Stomatology, Guangdong Medical College, Zhanjiang, Guangdong, China

      Jianping Huang

    5. MOE Key Laboratory of Regenerative Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China

      Wayne Y. W. Lee & Gang Li

    Authors
    1. Sien Lin
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Jianping Huang
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Ziwei Fu
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Yanlong Liang
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Haiyou Wu
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Liangliang Xu
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Yuxin Sun
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Wayne Y. W. Lee
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Tie Wu
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Ling Qin
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Liao Cui
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Gang Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Liao Cui or Gang Li.

    Additional information

    Sien Lin and Jianping Huang have contributed equally to this study.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Lin, S., Huang, J., Fu, Z. et al. The Effects of Atorvastatin on the Prevention of Osteoporosis and Dyslipidemia in the High-Fat-Fed Ovariectomized Rats. Calcif Tissue Int 96, 541–551 (2015). https://doi.org/10.1007/s00223-015-9975-7

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00223-015-9975-7

    Keywords

    Search

    Navigation