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Age-dependent effects of atorvastatin on biochemical bone turnover markers: a randomized controlled trial in postmenopausal women

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Abstract

The use of HMG-CoA-reductase inhibitors (statins) has been associated with decreased risk of bone fractures in epidemiological studies. In vitro evidence suggests that statins may stimulate bone formation, but the data are still preliminary. We assessed the effects of the HMG-CoA-reductase inhibitor atorvastatin on biochemical parameters of bone metabolism in a multicenter, randomized, double-blind, placebo-controlled trial conducted between October 2001 and October 2002 in three hospital-based outpatient metabolism clinics. Forty-nine postmenopausal women, mean age 61 ± 5 years, mean time postmenopause 12.6 ± 8.8 years, were treated with atorvastatin, 20 mg per day (n=24) or matching placebos (n=25) for 8 weeks. Comparing the differences to baseline between the groups, there were no statistically significant effects of atorvastatin either on the bone formation markers intact osteocalcin and bone-specific alkaline phosphatase or on the bone resorption markers C-telopeptide and intact parathyroid hormone. The marker of bone fractures, undercarboxylated osteocalcin, was also unchanged. When analyzed in dependence of age, atorvastatin increased C-telopeptide and osteocalcin in the younger subjects, while it decreased them in older subjects. Most interestingly, in older subjects, atorvastatin caused a significant decrease in the ratio of C-telopeptide to osteocalcin, an indicator of bone remodeling, while the ratio was increased in younger subjects, suggesting beneficial effects on bone turnover exclusively in older individuals (approx. >63 years). In summary, the present data suggest that short-term treatment with atorvastatin may have age-dependent effects on biochemical markers of bone turnover in postmenopausal women.

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References

  1. LaRosa JC, He J, Vupputuri S (1999) Effects of statins on risk of coronary heart disease: a meta-analysis of randomized controlled trials. JAMA 282:2340–2346

    CAS  PubMed  Google Scholar 

  2. Schlienger RG, Meier CR (2003) HMG-CoA reductase inhibitors in osteoporosis—do they reduce the risk of fracture? Drugs Aging 20:321–336

    CAS  PubMed  Google Scholar 

  3. Chan MHM, Mak TWL, Chiu RWK, Chow C-C, Chan IHS, Lam CWK (2001) Simvastatin increases serum osteocalcin concentration in patients treated for hypercholesterolaemia. J Clin Endocrinol Metab 86:4556–4559

    Google Scholar 

  4. Chung YS, Lee MD, Lee SK, Kim HM, Fitzpatrick LA (2000) HMG-CoA reductase inhibitors increase BMD in type 2 diabetes mellitus patients. J Clin Endocrinol Metab 85:1137–1142

    Google Scholar 

  5. Bauer DC, Sklarin PM, Stone KL, Black DM, Nevitt MC, Ensrud KE, Arnaud CD, Genant HK, Garnero P, Delmas PD, Lawaetz H, Cummings SR (1999) Biochemical markers of bone turnover and prediction of hip bone loss in older women: the study of osteoporotic fractures. J Bone Miner Res 14:1404–1410

    CAS  PubMed  Google Scholar 

  6. Edwards CJ, Hart DJ, Spector TD (2000) Oral statins and increased bone mineral density in postmenopausal women. Lancet 355:2218–2219

    Article  CAS  PubMed  Google Scholar 

  7. Watanabe S, Fukomoto S, Takeuchi Y, Nakano T, Fujita T (2000) Effects of one year treatment with statins on bone mass and metabolism (abstract). J Bone Miner Res 15[Suppl]:S194

  8. Watanabe S, Fukomoto S, Takeuchi Y, Nakano T, Fujita T (2000) Effects of 1-year treatment with fluvastatin or pravastatin on bone. Am J Med 110:584–587

    Article  Google Scholar 

  9. Bauer DM, Mundy GR, Jamal SA, Black DM, Cauley JA, Duong T, Cummings SR (1999) Statin use, bone mass and fracture: an analysis of two prospective studies (abstract). J Bone Miner Res 14[Suppl]:S179

  10. Chan KA, Andrade SE, Boles M, Buist DSM, 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 

  11. Meier CR, Schlienger RG, Kraenzlin ME, Schlegel B, Jick H (2000) HMG-CoA reductase inhibitors and the risk of fractures. JAMA 283:3205–3210

    CAS  PubMed  Google Scholar 

  12. Wang PS, Solomon DH, Mogun H, Avorn J (2000) HMG-CoA reductase inhibitors and the risk of hip fractures in elderly patients. JAMA 283:3211–3216

    CAS  PubMed  Google Scholar 

  13. Pasco JA, Kotowicz MA, Henry MJ, Sanders KM, Nicholson GC (2002) Statin use, bone mineral density, and fracture risk: Geelong Osteoporosis Study. Arch Int Med 162:537–540

    Article  CAS  Google Scholar 

  14. Rejnmark L, Buus NH, Vestergaard P, Andreasen F, Larsen ML, Mosekilde L (2002) Statins decrease bone turnover in postmenopausal women: a cross-sectional study. Eur J Clin Invest 32:581–589

    Article  CAS  PubMed  Google Scholar 

  15. Bjarnason NH, Riis BJ, Christiansen C (2001) The effect of fluvastatin on parameters of bone remodeling. Osteoporos Int 12:380–384

    Article  CAS  PubMed  Google Scholar 

  16. Sirola J, Sirola J, Honkanen R, Kroger H, Jurvelin JS, Maenpaa P, Saarikoski S (2002) Relation of statin use and bone loss: a prospective population-based cohort study in early postmenopausal women. Osteoporos Int 13:537–541

    CAS  PubMed  Google Scholar 

  17. LaCroix AZ, Cauley JA, Jackson R, McGowen J, Pettinger M, Hsia J, Chen Z, Lewis CE, Bauer D, Daugherty S, McNeeley SG, Passero M (2000) Does statin use reduce risk of fracture in postmenopausal women? Results from women’s health initiative study (WHI-OS) (abstract). J Bone Miner Res 15:S155

    Google Scholar 

  18. van Staa T-P, Wegman S, de Fries F, Leufkens B, Cooper C (2001) Use of statins and risk of fractures. JAMA 285:1850–1855

    PubMed  Google Scholar 

  19. Reid IR, Hague W, Emberson J, Baker J, Tonkin A, Hunt D, MacMahon S, Sharpe N, The LIPID Study Group (2001) Effect of pravastatin on frequency of fracture in the LIPID study: secondary analysis of a randomized controlled trial. Lancet 357:509–512

    Article  CAS  PubMed  Google Scholar 

  20. Petersen TR, Kjekshus J (2000) Statin drugs and the risk of fracture. JAMA 284:1921–1922

    CAS  Google Scholar 

  21. Heart Protection Study Collaborative Group (2002) MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360:7–22

    Article  PubMed  Google Scholar 

  22. Ray WA, Daugherty JR, Griffin MR (2002) Lipid-lowering agents and the risk of hip fracture in a Medicaid population. Injury Prevention 8:276–279

    Article  CAS  PubMed  Google Scholar 

  23. LaCroix AZ, Cauley JA, Pettinger M, Hsia J, Bauer DC, McGowan J, Chen Z, Lewis CE, McNeeley SG, Passaro MD, Jackson RD (2003) Statin use, clinical fracture, and bone density in postmenopausal women: Results from the Women’s Health Initiative Observational Study. Ann Int Med 139:97–104

    CAS  PubMed  Google Scholar 

  24. Cummings SR, Bauer DC (2000) Do statins prevent both cardiovascular disease and fracture? JAMA 283:3255–3257

    CAS  PubMed  Google Scholar 

  25. Hamelin BA, Turgeon J (1998) Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol Sci 19:26–37

    CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  27. van Beek E, Loewik C, van der Pluim G, Papapoulos S (1999) The role of geranylgeranylation in bone resorption and its suppression by bisphosphonates in fetal bone explants in vivo: a clue to the mechanism of action of nitrogen-containing bisphosphonates. J Bone Miner Res 14:722–729

    Google Scholar 

  28. Staal A, Frith JC, French MH, Swartz J, Gungor T, Harrity TW, Tamasi J, Rogers MJ, Feyen JH (2003) The ability of statins to inhibit bone resorption is directly related to their inhibitory effect on HMG-CoA reductase activity. J Bone Miner Res 18:88–96

    CAS  PubMed  Google Scholar 

  29. Chesnut CH, Silverman S, Andriano K, Genant H, Gimona A, Harris S, Kiel D, LeBoff M, Maricic M, Miller P, Moniz C, Peacock M, Richardson P, Watts N, Baylink D (2000) A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: The Prevent Recurrence of Osteoporotic Fractures Study. Am J Med 109:267–276

    Article  CAS  PubMed  Google Scholar 

  30. Bauer DC (2003) HMG CoA reductase inhibitors and the skeleton: a comprehensive review. Osteoporos Int 14:273–282

    Article  CAS  PubMed  Google Scholar 

  31. Klausen T, Breum L, Sorensen HA, Schifter S, Sonne B (1993) Plasma levels of parathyroid hormone, vitamin D, calcitonin, and calcium in association with endurance exercise. Calcif Tissue Int 52:205–208

    CAS  PubMed  Google Scholar 

  32. Fall PM, Kennedy D, Smith JA, Seibel MJ, Raisz LG (2000) Comparison of serum and urine assays for biochemical markers of bone resorption in potsmenopausal women with and without hormone replacement therapy and in men. Osteoporos Int 11:481–485

    Article  CAS  PubMed  Google Scholar 

  33. Woitge HW, Pecherstorfer M, Li Y, Keck AV, Horn E, Ziegler R, Seibel MJ (1999) Novel serum markers of bone resorption: clinical assessment and comparisons with established urinary indices. J Bone Miner Res 14:792–801

    CAS  PubMed  Google Scholar 

  34. Szulc P, Chapuy P, Meunier J, Delmas PD (1993) Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture in elderly women. J Clin Invest 91:1769–1774

    CAS  PubMed  Google Scholar 

  35. Seibel MJ, Robins SP, Bilezikian JP (1997) Serum undercarboxylated osteocalcin and the risk of hip fracture. J Clin Endocrinol Metab 82:717–718

    CAS  PubMed  Google Scholar 

  36. Pedrazzoni M, Alfano FS, Gatti C, Fantuzzi M, Girasole G, Campanini C, Basini G, Passeri M (1995) Acute effects of bisphosphonates on new and traditional markers of bone resorption. Calcif Tissue Int 57:25–29

    CAS  PubMed  Google Scholar 

  37. Gamero P, Shih WJ, Gineyts E, Karpf DB, Delmas PD (1994) Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment. J Clin Endocrinol Metab 79:1693–1700

    CAS  PubMed  Google Scholar 

  38. Balk EM, Lau J, Goudas LC, Jordan HS, Kupelnick B, Kim LU, Karas RH (2003) Effects of statins on nonlipid serum markers associated with cardiovascular disease. Ann Int Med 139:670–682

    CAS  PubMed  Google Scholar 

  39. Looker AC, Harris TB, Wahner HW (1992) Assessing hip fracture risk in a population-based health survey: the NHANES III osteoporosis component. Aging (Milano) 4:53–60

  40. Melton LJ, Khosla S, Atkinson EJ, O’Fallon WM, Riggs BL (1997) Relationship of bone turnover to bone density and fractures. J Bone Miner Res 12:1083–1091

    PubMed  Google Scholar 

  41. Garnero P, Hausherr E, Chapuy MC, Marcelli C, Grandjean H, Muller C, Cormier C, Breart G, Meunier PJ, Delmas PD (1996) Markers of bone resorption predict hip fracture in elderly women: the EPIDOS Prospective Study. J Bone Miner Res 11:1531–1538

    CAS  PubMed  Google Scholar 

  42. van Daele PL, Seibel MJ, Burger H, Hofman A, Grobbee DE, van Leeuwen JP, Birkenhager JC, Pols HA (1996) Case-control analysis of bone resorption markers, disability, and hip fracture risk: the Rotterdam study. Br Med J 312:482–483

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  44. Stein EA, Farnier M, Waldstreicher J, Mercuri M (2001) Effects of statins on biomarkers of bone metabolism: a randomised trial. Nutr Metab Cardiovasc Dis 11:84–87

    CAS  PubMed  Google Scholar 

  45. Streja L, Packard CJ, Shepherd J, Cobbe S, Ford I, WOSCOPS Group (2002) Factors affecting low-density lipoprotein and high-density lipoprotein cholesterol response to pravastatin in the West of Scotland Coronary Prevention Study (WOSCOPS). Am J Cardiol 90:731–736

    Article  CAS  PubMed  Google Scholar 

  46. Seeman E (2002) Pathogenesis of bone fragility in women and men. Lancet 359:1841–1850

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank Dr Michael Holzem for clinical support, Claudia Krapf for her organizational skills, and Adelheid Schuch for her excellent technical support. Funding/support: None of the authors declared any conflicts of interest. This work was supported in part by funds from the Institute for Clinical Research and Department of Clinical Pharmacology, Center for Cardiovascular Diseases, Rotenburg an der Fulda; Medical Policlinic, University of Bonn; and Department of Nutrition, University of Bonn. The study was entirely independent of funds from the pharmaceutical industry and other commercial enterprises.

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Correspondence to Heiner K. Berthold.

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Berthold, H.K., Unverdorben, S., Zittermann, A. et al. Age-dependent effects of atorvastatin on biochemical bone turnover markers: a randomized controlled trial in postmenopausal women. Osteoporos Int 15, 459–467 (2004). https://doi.org/10.1007/s00198-004-1598-1

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  • DOI: https://doi.org/10.1007/s00198-004-1598-1

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