Effect of Statins on Bone Turnover Markers

  • Magdalena Fernández García
  • José L. HernándezEmail author
Reference work entry
Part of the Biomarkers in Disease: Methods, Discoveries and Applications book series (BDMDA)


The link between statins, the most prescribed drugs worldwide, and the bone remodeling process have been recently suggested. Thus, there is growing evidence about an anabolic and even anticatabolic effect of statins on bone metabolism.

Bone turnover markers (BTMs) reflect the remodeling status and provide a dynamic assessment of the skeleton which may complement the information obtained by bone mineral density (BMD) assessment. However, the effect of statins on BTMs has been reported in a few randomized controlled trials, with contradictory results, mainly based on its small sample size and shorter duration of treatment. Most of them concluded that serum BTMs are lower in patients on statins than in nonusers. Overall, decreases in BTMs have been more evident in subjects receiving the more lipophilic statins, especially when using for long periods of time. Simvastatin and atorvastatin have been the most studied statins regarding its effects on bone metabolism. In this chapter, the main data on the effect of all the marketed statins on BTMs will be reviewed.


Statins 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors Bone remodeling Bone turnover markers Alkaline phosphatase Procollagen type I N-terminal peptide C-terminal type I collagen telopeptide Osteocalcin Bone morphogenetic protein 

List of Abbreviations


Alkaline phosphatase


Primary alveolar osteoblasts


Area under the curve


Bone mineral density


Bone morphogenetic protein


Bone morphogenetic protein-2




Bone-specific alkaline phosphatase


Bone turnover markers


Carboxy-terminal cross-linked telopeptide of type 1 collagen


Farnesyl pyrophosphate


Geranylgeranyl pyrophosphate

HMG-CoA reductase

3-Hydroxy-3-methylglutaryl coenzyme A reductase


The International Osteoporosis Foundation


Low-density lipoprotein


Messenger ribonucleic acid


Not available




Amino-terminal cross-linked telopeptide of type 1 collagen








N-Terminal propeptide of type I procollagen


Periodontal ligament cells


Receptor activator of nuclear factor-kappa B ligand

Terminal half life


Total alkaline phosphatase


Transforming growth factor-beta


Tartrate-resistant acid phosphatase


Undercarboxylated osteocalcin


Very low-density lipoprotein




  1. Ayukawa Y, Ogino Y, Moriyama Y, et al. Simvastatin enhances bone formation around titanium implants in rat tibiae. J Oral Rehabil. 2010;37:123–30.CrossRefPubMedGoogle Scholar
  2. Bauer DC. HMG CoA reductase inhibitors and the skeleton: a comprehensive review. Osteoporos Int. 2003;14:273–82.CrossRefPubMedGoogle Scholar
  3. Bauer DC, Mundy GR, Jamal SA, et al. 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.CrossRefPubMedGoogle Scholar
  4. Berthold HK, 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. 2004;15:459–67.CrossRefPubMedGoogle Scholar
  5. Bjarnason NH, Riis BJ, Christiansen C. The effect of fluvastatin on parameters of bone remodeling. Osteoporos Int. 2001;12:380–4.CrossRefPubMedGoogle Scholar
  6. Bone HG, Kiel DP, Lindsay RS, 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;92:4671–7.CrossRefPubMedGoogle Scholar
  7. Braatvedt GD, Bagg W, Gamble G, et al. The effect of atorvastatin on markers of bone turnover in patients with type 2 diabetes. Bone. 2004;35:766–70.CrossRefPubMedGoogle Scholar
  8. Chan MH, Mak TW, Chiu RW, et al. Simvastatin increases serum osteocalcin concentration in patients treated for hypercholesterolaemia. J Clin Endocrinol Metab. 2001;86:4556–9.CrossRefPubMedGoogle Scholar
  9. Chen ZG, Cai HJ, Jin X, et al. Effects of atorvastatin on bone mineral density (BMD) and bone metabolism in elderly males with osteopenia and mild dyslipidemia: a 1-year randomized trial. Arch Gerontol Geriatr. 2014;59:515–21.CrossRefPubMedGoogle Scholar
  10. Chuengsamarn S, Rattanamongkoulgul S, Suwanwalaikorn S, et al. Effects of statins vs. non-statin lipid-lowering therapy on bone formation and bone mineral density biomarkers in patients with hyperlipidemia. Bone. 2010;46:1011–5.CrossRefPubMedGoogle Scholar
  11. Du Z, Chen J, Yan F, et al. Serum bone formation marker correlation with improved osseointegration in osteoporotic rats treated with simvastatin. Clin Oral Implants Res. 2013;24:422–7.CrossRefPubMedGoogle Scholar
  12. Farley JR, Chesnut 3rd CH, Baylink DJ. Improved method for quantitative determination in serum of alkaline phosphatase of skeletal origin. Clin Chem. 1981;27:2002–7.Google Scholar
  13. Funk JL, Chen J, Downey KJ, et al. Bone protective effect of simvastatin in experimental arthritis. J Rheumatol. 2008;35:1083–91.PubMedGoogle Scholar
  14. Gao YH, Shinki T, Yuasa T, et al. Potential role of Cbfa1, an essential transcriptional factor for osteoblast differentiation, in osteoclastogenesis: regulation of mRNA expression of osteoclast differentiation factor (ODF). Biochem Biophys Res Commun. 1998;252:697–702.CrossRefPubMedGoogle Scholar
  15. Gradosova I, Zivna H, Palicka V, et al. Protective effect of atorvastatin on bone tissue in orchidectomised male albino Wistar rats. Eur J Pharmacol. 2012;679:144–50.CrossRefPubMedGoogle Scholar
  16. Hamelin BA, Turgeon J. Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMGCoA reductase inhibitors. Trends Pharmacol Sci. 1998;19:26–37.CrossRefPubMedGoogle Scholar
  17. Hatzigeorgiou C, Jackson JL. Hydroxymethylglutaryl coenzyme A reductase inhibitors and osteoporosis: a meta-analysis. Osteoporos Int. 2005;16:990–6.CrossRefPubMedGoogle Scholar
  18. Hay E, Lemonnier J, Fromigué O, et al. Bone morphogenetic protein-2 promotes osteoblast apoptosis through a Smad independent, protein kinase C-dependent signaling pathway. J Biol Chem. 2001;276:29028–36.CrossRefPubMedGoogle Scholar
  19. Hernández JL, Olmos JM, Romaña G, et al. Bone turnover markers in statins users: a population based analysis from the Camargo Cohort Study. Maturitas. 2013;75:67–73.CrossRefPubMedGoogle Scholar
  20. Hernández JL, Olmos JM, Romaña G, et al. Bone mineral density in statin users: a population-based analysis from a Spanish cohort. J Bone Miner Metab. 2014;32:184–91.CrossRefPubMedGoogle Scholar
  21. Hsia J, Morse M, Levin V. Effect of simvastatin on bone markers in osteopenic women: a placebo-controlled, dose-ranging trial [ISRCTN85429598]. BMC Musculoskelet Disord. 2002;3:7.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Itoh K, Udagawa N, Katagiri T, et al. Bone morphogenetic protein 2 stimulates osteoclast differentiation and survival supported by receptor activator of nuclear factor- k B ligand. Endocrinology. 2001;142:3656–62.CrossRefPubMedGoogle Scholar
  23. Jadhav SB, Narayana Murthy PS, Singh MM, et al. Distribution of lovastatin to bone and its effect on bone turnover in rats. J Pharm Pharmacol. 2006;58:1451–8.CrossRefPubMedGoogle Scholar
  24. Kanazawa I, Yamaguchi T, Yamauchi M, et al. Rosuvastatin increased serum osteocalcin levels independent of its serum cholesterol-lowering effect in patients with type 2 diabetes and hypercholesterolemia. Intern Med. 2009;48:1869–73.CrossRefPubMedGoogle Scholar
  25. Kaneko H, Arakawa T, Mano H, et al. Direct stimulation of osteoclastic bone resorption by bone morphogenetic protein (BMP)-2 and expression of BMP receptors in mature osteoclasts. Bone. 2000;27:479–86.CrossRefPubMedGoogle Scholar
  26. Kawabata M, Miyazono K. Bone morphogenetic proteins. In: Canalis E, editor. Skeletal growth factors. Philadelphia: Lippincott, Williams & Wilkins; 2000. p. 269–90.Google Scholar
  27. Kuzuya M, Suzuki Y, Asai T, et al. Atorvastatin, 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, reduces bone resorption in the elderly. J Am Geriatr Soc. 2003;51:1677–8.CrossRefPubMedGoogle Scholar
  28. Kwak B, Mulhaupt F, Myit S, et al. Statins as a newly recognized type of immunomodulator. Nat Med. 2000;6:1399–402.CrossRefPubMedGoogle Scholar
  29. Leboy PS, Grasso-Knight G, D’Angelo M, et al. Smad-Runx interactions during chondrocyte maturation. J Bone Joint Surg Am. 2001;83:S15–22.CrossRefPubMedGoogle Scholar
  30. Lee KS, Kim HJ, Li QL, et al. Runx2 is a common target of transforming growth factor β1 and bone morphogenetic protein 2, and cooperation between Runx2 and Smad5 induces osteoblast-specific gene expression in the pluripotent mesenchymal precursor cell line C2C12. Mol Cell Biol. 2000;20:8783–92.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Liu S, Bertl K, Sun H, et al. Effect of simvastatin on the osteogenetic behavior of alveolar osteoblasts and periodontal ligament cells. Hum Cell. 2012;25:29–35.CrossRefPubMedGoogle Scholar
  32. Luckman SP, Hughes DE, Coxon FP, et al. 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.CrossRefPubMedGoogle Scholar
  33. Majima T, Komatsu Y, Fukao A, et al. Short-term effects of atorvastatin on bone turnover in male patients with hypercholesterolemia. Endocr J. 2007a;54:145–51.CrossRefPubMedGoogle Scholar
  34. Majima T, Shimatsu A, Komatsu Y, et al. Short-term effects of pitavastatin on biochemical markers of bone turnover in patients with hypercholesterolemia. Intern Med. 2007b;46:1967–73.CrossRefPubMedGoogle Scholar
  35. Montagnani A, Gonnelli S, Cepollaro C, et al. Effect of simvastatin treatment on bone mineral density and bone turnover in hypercholesterolemic postmenopausal women: a 1-year longitudinal study. Bone. 2003;32:427–33.CrossRefPubMedGoogle Scholar
  36. Mostaza JM, et al. Pravastatin therapy increases procollagen I N-terminal propeptide (PINP), a marker of bone formation in post-menopausal women. In: Clinica chimica acta; international journal of clinical chemistry; 2001. vol. 308(1-2), p. 133–7.Google Scholar
  37. Mostaza JM, De la Piedra C, Curiel MD, et al. Pravastatin therapy increases procollagen I N-terminal propeptide (PINP), a marker of bone formation in post-menopausal women. Clin Chim Acta. 2010;308:133–7.CrossRefGoogle Scholar
  38. Mundy G, Garrett R, Harris S, et al. Stimulation of bone formation in vitro and in rodents by statins. Science. 1999;286:1946–9.CrossRefPubMedGoogle Scholar
  39. Ozkaynak E, Schnegelsberg PN, Jin DF, et al. Osteogenic protein-2. J Biol Chem. 1992;267:25220–7.PubMedGoogle Scholar
  40. Pereira RMR, Delany AM, Canalis E. Cortisol inhibits the differentiation and apoptosis of osteoblasts in culture. Bone. 2001;28:484–90.CrossRefPubMedGoogle Scholar
  41. Puri V, Meeta MD. Role of biochemical markers of bone turnover. In: Meeta MD, editor. Postmenopausal osteoporosis: basic and clinical concepts. 1st ed. India: Jaypee Brothers Medical Publishers; 2013. p. 93–101.Google Scholar
  42. Rehder DS, Gundberg CM, Booth SL, et al. Gamma-carboxylation and fragmentation of osteocalcin in human serum defined by mass spectrometry. Mol Cell Proteomics. 2015;14:1546–55.CrossRefPubMedPubMedCentralGoogle Scholar
  43. Rejnmark L, Buus NH, Vestergaard P, et al. Statins decrease bone turnover in postmenopausal women: a cross-sectional study. Eur J Clin Invest. 2002;32:581–9.CrossRefPubMedGoogle Scholar
  44. Rosenson RS, Tangney CC, Langman CB, et al. Short-term reduction in bone markers with high-dose simvastatin. Osteoporos Int. 2005;16:1272–6.CrossRefPubMedGoogle Scholar
  45. Ruiz-Gaspa S, Nogues X, Enjuanes A, et al. Simvastatin and atorvastatin enhance gene expression of collagen type 1 and osteocalcin in primary human osteoblasts and MG-63 cultures. J Cell Biochem. 2007;101:1430–8.CrossRefPubMedGoogle Scholar
  46. Stein EA, Farnier M, Waldstreicher J, et al. Effects of statins on biomarkers of bone metabolism: a randomised trial. Nutr Metab Cardiovasc Dis. 2001;11:84–7.PubMedGoogle Scholar
  47. Tikiz C, Unlü Z, Tikiz H, et al. The effect of simvastatin on serum cytokine levels and bone metabolism in postmenopausal subjects: negative correlation between TNF-alpha and anabolic bone parameters. J Bone Miner Metab. 2004;22:365–71.CrossRefPubMedGoogle Scholar
  48. Tikiz C, Tikiz H, Taneli F, et al. 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.CrossRefPubMedGoogle Scholar
  49. Uzzan B, Cohen R, Nicolas P, et al. Effects of statins on bone mineral density: a meta-analysis of clinical studies. Bone (New York). 2007;40:1581–7.Google Scholar
  50. Varghese S, Canalis E. Regulation of collagenase-3 by bone morphogenetic protein-2 in bone cell cultures. Endocrinology. 1997;138:1035–40.CrossRefPubMedGoogle Scholar
  51. Vasikaran S, Eastell R, Bruyère O, Bone Marker Standards Working Group, et al. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int. 2011;22:391–420.CrossRefPubMedGoogle Scholar
  52. Wan M, Shi X, Feng X, et al. Transcriptional mechanisms of bone morphogenetic protein-induced osteoprotegrin gene expression. J Biol Chem. 2001;276:10119–25.CrossRefPubMedGoogle Scholar
  53. Wang EA, Rosen V, D’Alessandro JS, et al. Recombinant human bone morphogenetic protein induces bone formation. Proc Natl Acad Sci U S A. 1990;87:2220–4.CrossRefPubMedPubMedCentralGoogle Scholar
  54. Watanabe S, Fukumoto S, Takeuchi Y, et al. Effects of 1-year treatment with fluvastatin or pravastatin on bone. Am J Med. 2001;110:584–7.CrossRefPubMedGoogle Scholar
  55. Weitz-Schmidt G, Welzenbach K, Brinkmann V, et al. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med. 2001;7:687–92.CrossRefPubMedGoogle Scholar
  56. Woo JT, Kasai S, Stern PH, et al. 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.CrossRefPubMedGoogle Scholar
  57. Wozney JM, Rosen V, Celeste AJ, et al. Novel regulators of bone formation: molecular clones and activities. Science. 1988;242:1528–34.CrossRefPubMedGoogle Scholar
  58. Yue J, Zhang X, Dong B, et al. Statins and bone health in postmenopausal women: a systematic review of randomized controlled trials. Menopause. 2010;17:1071–9.CrossRefPubMedGoogle Scholar
  59. Zhang Y, Bradley AD, Wang D, et al. Statins, bone metabolism and treatment of bone catabolic diseases. Pharmacol Res. 2014;88:53–61.CrossRefPubMedGoogle Scholar
  60. Zhao W, Byrne MH, Boyce BF, et al. Bone resorption induced by parathyroid hormone is strikingly diminished in collagenase-resistant mutant mice. J Clin Invest. 1999;103:517–24.CrossRefPubMedPubMedCentralGoogle Scholar
  61. Zhou Q, Liao JK. Pleiotropic effects of statins. Basic research and clinical perspectives. Circ J. 2010;74:818–26.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2017

Authors and Affiliations

  • Magdalena Fernández García
    • 1
  • José L. Hernández
    • 1
    Email author
  1. 1.Bone Metabolism Unit, Department of Internal MedicineHospital Marqués de Valdecilla, University of CantabriaSantanderSpain

Personalised recommendations