Statins and osteoporosis

Authors: Kashtalap V.V.1,2, 2, Khryachkova O.N.1, Barbarash O.L.1,2, 2

Company: 1 Research Institute for Complex Issues of Cardiovascular Diseases; Sosnovyy bul’var, 6, Kemerovo, 650002, Russian Federation;
2 Kemerovo State University; ulitsa Krasnaya, 6, Kemerovo, 650043, Russian Federation

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DOI: https://doi.org/10.15275/kreatkard.2016.04.06

For citation: V.V. Kashtalap, O.N. Khryachkova, O.L. Barbarash. Statins and osteoporosis. Creative Cardiology. 2016; 10 (4): 317-323 (in Russ.).

Keywords: osteoporosis atherosclerosis statins bone mineral density fractures

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Abstract

The review presents the data on the relationships of osteopenic syndrome with dyslipidemia and coronary atherosclerosis. The possible molecular mechanisms of realization of the effects of statins in regard to the bone mineral density were discussed. For a compilation of the review article we used the available materials from foreign library databases (Library's MEDLINE/PubMed database).

References

  1. Dawson-Hughes B.D., Lindsay R., Khosla S., Melton L.J. III, Favus M., Baim S. Clinicians's guide to prevention and treatment of osteoporosis. Washington, DC: National Osteoporosis Foundation; 2008.
  2. Mandal C.C. High cholesterol deteriorates bone health: new insights into molecular mechanisms. Front. Endocrinol. 2015; 6: 165. DOI: 10.3389/fendo.2015.00165.
  3. Hernández J.L., Olmos J.M., Romana G. Bone mineral density in statin users: a population-based analysis from a Spanish cohort. J. Bone Miner. Metab. 2014; 32: 184–91.
  4. Sennerby U., Melhus H., Gedeborg R. Cardiovascular diseases and risk of hip fracture. JAMA. 2009; 302: 1666–73.
  5. Lopez A.D., Murray C.C. The global burden of disease, 1990–2020. Nat. Med. 1998; 4: 1241–3.
  6. Vertkin A.L., Naumov A.V., Ivanov V.S. Osteoporosis in patients with cardiovascular diseases. Sovremennaya revmatologiya. 2008; 1: 52–9 (in Russ.).
  7. Reginster J.Y., Burlet N. Osteoporosis: a still increasing prevalence. Bone. 2006; 38: S4–S9.
  8. Siris E.S., Miller P.D., Barrett-Connor E., Faulkner K.G., Wehren L.E., Abbott T.A. et al. Identification and fracture outcomes of undiagnosed low bone mineral density in postmenopausal women: results from the National Osteoporosis Risk Assessment. JAMA. 2001; 286 (22): 2815–22.
  9. Makovey J., Chen J.S., Hayward C., Williams F.M., Sambrook P.N. Association between serum cholesterol and bone mineral density. Bone. 2009; 44: 208–13. DOI: 10.1016/j.bone.2008.09.020.
  10. Kim K.-C., Shin D.-H., Lee S.-Y., Im J.-A., Lee D.-C. Relation between obesity and bone mineral `density and vertebral fractures in Korean postmenopausal women. Yonsei Med. J. 2010; 51: 857–63. DOI: 10.3349/ymj.2010.51.6.857.
  11. Kim Y.-H., Nam G.-E., Cho K.-H., Choi Y.S., Kim S.-M., Han B.-D. Low bone mineral density is associated with dyslipidemia in South Korean men: the 2008-2010 Korean National Health and Nutrition Examination Survey. Endocr. J. 2013; 60: 1179–89. DOI: 10.1507/endocrj.EJ13-0224.
  12. Jeong T.-D., Lee W., Choi S.-E., Kim J.S., Kim H.-K., Bae S.J. Relationship between serum total cholesterol level and serum biochemical bone turnover markers in healthy pre-and postmenopausal women. Biomed. Res. Int. 2014; 398397. DOI: 10.1155/2014/398397.
  13. Parhami F., Tintut Y., Beamer W.G., Gharavi N., Goodman W., Demer L.L. Atherogenic high-fat diet reduces bone mineralization in mice. J. Bone Miner. Res. 2001; 16: 182–8. DOI: 10.1359/jbmr.2001.16.1.182 10.
  14. Esposito K., Capuano A., Sportiello L., Giustina A., Giugliano D. Should we abandon statins in the prevention of bone fractures? Endocrine. 2013. DOI: 10.1007/s12020-013-9924-z.
  15. Yamaguchi T., Sugimoto T., Yano S., Yamauchi M., Sowa H., Chen Q., Chihara K. Plasma lipids and osteoporosis in postmenopausal women. Endocr. J. 2002; 49 (2): 211–7.
  16. Ahmed L.A., Schirmer H., Berntsen G.K., Fønnebø V., Joakimsen R.M. Features of the metabolic syndrome and the risk of non-vertebral fractures: the Tromsø study. Osteoporos. Int. 2006; 17 (3): 426–32.
  17. Sivas F., Alemdaroˇglu E., Elverici E., Kulug T., Ozoran K. Serum lipid profile: its relationship with osteoporotic vertebrae fractures and bone mineral density in Turkish postmenopausal women. Rheumatol. Int. 2009; 29 (8): 885–90.
  18. Szulc P., Varennes A., Delmas P.D., Goudable J., Chapurlat R. Men with metabolic syndrome have lower bone mineral density but lower fracture risk – the MINOS study. J. Bone Miner. Res. 2010; 25 (6): 1446–54.
  19. Trimpou P., Odén A., Simonsson T., Wilhelms L., Landin-Wilhelmsen K. High serum total cholesterol is a long-term cause of osteoporotic fracture. Osteoporos. Int. 2011; 22 (5): 1615–20.
  20. Baldini V., Mastropasqua M., Francucci C., D'Erasmo E. Cardiovascular disease and osteoporosis. J. Endocrinol. Invest. 2004; 28: 69–72.
  21. Tankó L.B., Christiansen C., Cox D.A., Geiger M.J., McNabb M.A., Cummings S.R. Relationship between osteoporosis and cardiovascular disease in postmenopausal women. J. Bone Miner. Res. 2005; 20: 1912–20. DOI: 10.1359/JBMR.050711.
  22. Broussard D.L., Magnus J.H. Coronary heart disease risk and bone mineral density among U.S. women and men. J. Women's Health. 2008; 17: 479–90.
  23. Barbarash O.L., Lebedeva N.B., Kokov A.N., Novitskaya A.A., Hryachkova O.N., Voronkina A.V. et al. Decreased cathepsin K plasma level may reflect an association of osteopoenia/ osteoporosis with coronary atherosclerosis and coronary artery calcification in male patients with stable angina. Heart, Lung Circ. 2016; 25 (7): 691–7. DOI: 10.1016/j.hlc.2016.02.002.
  24. Cauley J.A., Barbour K.E., Harrison S.L., Cloonan Y.K., Danelson M.E., Ensurd K.E. et al. Inflammatory markers and the risk of hip and vertebral fractures in men: the osteoporotic fractures in men (MrOS). J. Bone Miner. Res. 2016. DOI: 10.1002/jbmr.2905.
  25. Pender A., Lloyd-Jones D.M., Stone N.J., Greenland P. Refining statin prescribing in lower-risk individuals informing risk/benefit decisions. JACC. 2016; 68 (15): 1690–7.
  26. Ridker P. Is statin monotherapy the perfect polypill? Circulation. 2016; 134: 91–3.
  27. Silverman M.G., Ference B.A., Im K., Wiviott S.D., Giugliano R.P., Grundy S.M. et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions. A systematic review and meta-analysis. JAMA. 2016; 316 (12): 1289–97. DOI: 10.1001/jama.2016.13985.
  28. Mundy G., Garrett R., Harris S., Chan J., Chen D., Rossini G. Stimulation of bone formation in vitro and in rodents by statins. Science. 1999; 286: 1946–9. DOI: 10.1126/science.286.5446.1946.
  29. Edwards C., Hart D., Spector T. Oral statins and increased bone-mineral density in postmenopausal women. Lancet. 2000; 355: 2218–9. DOI: 10.1016/S0140-6736(00)02408-9.
  30. Meier C.R., Schlienger R.G., Kraenzlin M.E., Schlegel B., Jick H. HMG-CoA reductase inhibitors and the risk of fractures. JAMA. 2000; 283: 3205–10. DOI: 10.1001/jama.283.24.3205.
  31. Dai L., Xu M., Wu H., Xue L., Yuan D., Wang Y. et al. The functional mechanism of simvastatin in experimental osteoporosis. J. Bone Miner. Metab. 2014. DOI: 10.1007/s00774-014-0638-y.
  32. Rosen C.J., Bilezikian J.P. Clinical review 123: anabolic therapy for osteoporosis. J. Clin. Endocrinol. Metab. 2001; 86: 957–64.
  33. Bauer D.C., Mundy G.R., Jamal S.A. Use of statins and fracture: results of 4 prospective studies and cumulative meta-analysis of observational studies and controlled trials. Arch. Intern. Med. 2004; 164: 146–52.
  34. Hatzigeorgiou C., Jackson J.L. Hydroxymethylglutaryl-coenzyme A reductase inhibitors and osteoporosis: a meta-analysis. Osteoporos Int. 2005; 16: 990–6.
  35. Uzzan B., Cohen R., Nicolas P., Cucherat M., Perret G.Y. Effects of statins on bone mineral density: a meta-analysis of clinical studies. Bone. 2007; 40: 1581–7.
  36. Yue J., Zhang X., Dong B., Yang M. Statins and bone health in postmenopausal women: a systematic review of randomized controlled trials. Menopause. 2010; 17: 1071–9.
  37. Liu J., Zhu L.P., Yang X.L., Huang H.L., Ye D.Q. HMG-CoA reductase inhibitors (statins) and bone mineral density: a meta-analysis. Bone. 2013; 54: 151–6.
  38. Bone H.G., Kiel D.P., Lindsay R.S., Lewiecki E.M., Bolognese M.A., Leary E.T. et al. Effects of atorvastatin on bone in postmenopausal women with dyslipidemia: a double-blind, placebo-controlled, dose-ranging trial. J. Clin. Endocrinol. Metab. 2007; 92 (12): 4671–7.
  39. Ohnaka K., Shimoda S., Nawata H. Pitavastatin enhanced BMP-2 and osteocalcin expression by inhibition of rho-associated kinase in human osteoblasts. Biochem. Biophys. Res. Commun. 2001; 287: 337–42.
  40. Woo J.T., Kasai S., Stern P.H., Nagai K. Compactin suppresses bone resorption by inhibiting the fusion of perfusion osteoclasts and disrupting the actin ring in osteoclasts. J. Bone Miner. Res. 2000; 15: 650–62.
  41. Sathyapalan T., Shepherd J., Atkin S.L., Kilpatrick E.S. The effect of atorvastatin and simvastatin on vitamin D, oxidative stress and inflammatory marker concentrations in patients with type 2 diabetes: a crossover study. Diabetes Obes. Metab. 2013; 15: 767–9.
  42. Makariou S.E., Liberopoulos E.N., Agouridis A.P., Challa A., Elisaf M. Effect of rosuvastatin monotherapy and in combination with fenofibrate or Ω-3 fatty acids on serum vitamin D levels. J. Cardiovasc. Pharmacol. Ther. 2012; 17: 382–6.43. Hernández J.L., Olmos J.M., Romana G., Llorca J., Martínez J., Castillo J. et al. Influence of vitamin D status on the effect of statins on bone mineral density and bone turnover markers in postmenopausal women. J. Clin. Endocrinol. Metab. 2014; 99 (9): 3304–9. DOI: 10.1210/jc.2014-1102.
  43. Rejnmark L., Vestergaard P., Heickendorff L., Mosekilde L. Simvastatin does not affect vitamin D status, but low vitamin D levels are associated with dyslipidemia: results from a randomised, controlled trial. Int. J. Endocrinol. 2010; article locator 957174.
  44. Yavuz B., Ertugrul D.T., Cil H. Increased levels of 25 hydroxy vitamin D and 1,25-dihydroxy vitamin D after rosuvastatin treatment: a novel pleiotropic effect of statins? Cardiovasc. Drugs Ther. 2009; 23: 295–9.
  45. Mandal C.C., Ghosh-Choudhury N., Yoneda T., Choudhury G.G., Ghosh-Choudhury N. Simvasta 151–6.
  46. Bone H.G., Kiel D.P., Lindsay R.S., Lewiecki E.M., Bolognese M.A., Leary E.T. et al. Effects of atorvastatin on bone in postmenopausal women with dyslipidemia: a double-blind, placebo-controlled, dose-ranging trial. J. Clin. Endocrinol. Metab. 2007; 92 (12): 4671–7.
  47. Ohnaka K., Shimoda S., Nawata H. Pitavastatin enhanced BMP-2 and osteocalcin expression by inhibition of rho-associated kinase in human osteoblasts. Biochem. Biophys. Res. Commun. 2001; 287: 337–42.
  48. Woo J.T., Kasai S., Stern P.H., Nagai K. Compactin suppresses bone resorption by inhibiting the fusion of perfusion osteoclasts and disrupting the actin ring in osteoclasts. J. Bone Miner. Res. 2000; 15: 650–62.
  49. Sathyapalan T., Shepherd J., Atkin S.L., Kilpatrick E.S. The effect of atorvastatin and simvastatin on vitamin D, oxidative stress and inflammatory marker concentrations in patients with type 2 diabetes: a crossover study. Diabetes Obes. Metab. 2013; 15: 767–9.
  50. Makariou S.E., Liberopoulos E.N., Agouridis A.P., Challa A., Elisaf M. Effect of rosuvastatin monotherapy and in combination with fenofibrate or Ω-3 fatty acids on serum vitamin D levels. J. Cardiovasc. Pharmacol. Ther. 2012; 17: 382–6.
  51. Hernández J.L., Olmos J.M., Roma~na G., Llorca J., Martínez J., Castillo J. et al. Influence of vitamin D status on the effect of statins on bone mineral density and bone turnover markers in postmenopausal women. J. Clin. Endocrinol. Metab. 2014; 99 (9): 3304–9. DOI: 10.1210/jc.2014-1102.
  52. Rejnmark L., Vestergaard P., Heickendorff L., Mosekilde L. Simvastatin does not affect vitamin D status, but low vitamin D levels are associated with dyslipidemia: results from a randomised, controlled trial. Int. J. Endocrinol. 2010; article locator 957174.
  53. Yavuz B., Ertugrul D.T., Cil H. Increased levels of 25 hydroxy vitamin D and 1,25-dihydroxy vitamin D after rosuvastatin treatment: a novel pleiotropic effect of statins? Cardiovasc. Drugs Ther. 2009; 23: 295–9.
  54. Mandal C.C., Ghosh-Choudhury N., Yoneda T., Choudhury G.G., Ghosh-Choudhury N. Simvastatin prevents skeletal metastasis of breast cancer by an antagonistic interplay between p53 and CD44. J. Biol. Chem. 2011; 286: 11314-27. DOI: 10.1074/jbc.M110.193714.
  55. Ghosh-Choudhury N., Mandal C.C., Choudhury G.G. Statin-induced Ras acti-vation integrates the phosphatidylinositol 3-kinase signal to Akt and MAPK for bone morphogenetic protein-2 expression in osteoblast differentiation. J. Biol. Chem. 2007; 282: 4983–93. DOI: 10.1074/jbc.M606706200.
  56. Ruan F., Zheng Q., Wang, J. Mechanisms of bone anabolism regulated by statins. Biosci. Rep. 2012;32: 511–9.
  57. Luckman S.P., Hughes D.E., Coxon F.P., Graham R., Russell G., Rogers M.J. Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J. Bone Miner. Res. 1998; 13: 581–9. 50. Syed F., Khosla S. Mechanisms of sex steroid effects on bone. Biochem. Biophys. Res. Commun. 2005; 328: 688–96.
  58. Kaji H., Kanatani M., Sugimoto T., Chihara K. Statins modulate the levels of osteoprotegerin /receptor activator of NF kappa B ligand mRNA in mouse bone-cell cultures. Horm. Metab. Res. 2005; 37: 589–92.
  59. Reid I.R., Hague W., Emberson J., Baker J., Tonkin A., Hunt D. et al. 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. 2001; 357: 509–12.
  60. Reid I.R., Tonkin A., Cannon C.P. Comparison of the effects of pravastatin and atorvastatin on fracture incidence in the PROVE IT-TIMI 22 trial – secondary analysis of a randomized controlled trial. Bone. 2005; 37: 190–1.
  61. Tikiz C., Tikiz H., Taneli F., Gumuser G., Tuzun C. Effects of simvastatin on bone mineral density and remodeling parameters in postmenopausal osteopenic subjects: 1-year follow-up study. Clin. Rheumatol. 2005; 24: 447–52.

Chief Editor

Leo A. Bockeria, MD, PhD, DSc, Professor, Academician of Russian Academy of Sciences, President of Bakoulev National Medical Research Center for Cardiovascular Surgery