Skip to main content

Advertisement

Log in

A study of the effects of the aromatase inhibitors anastrozole and letrozole on bone metabolism in postmenopausal women with estrogen receptor-positive breast cancer

  • Clinical trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

ALIQUOT (Anastrozole vs. Letrozole, an Investigation of Quality Of Life and Tolerability) was a prospective, open-label, randomized pharmacodynamic study designed to assess the effects of aromatase inhibitors (AIs) on bone turnover in healthy postmenopausal women with estrogen receptor-positive breast cancer. Ninety-four patients were randomized to receive either 12 weeks of letrozole (2.5 mg; n = 42) followed by 12 weeks of anastrozole (1 mg), or 12 weeks of anastrozole (1 mg; n = 42) followed by 12 weeks of letrozole (2.5 mg). After completion of the study period, patients in the immediate adjuvant group were either switched to tamoxifen (n = 38) or continued on anastrozole or letrozole. In the beginning of the study, 42 patients had taken tamoxifen within 3 months. Patients taking drugs likely to affect bone metabolism, including bisphosphonates, were excluded. Eighty-four patients had complete sample measurements and were included in the analysis. Prior tamoxifen therapy resulted in a significantly lower mean baseline procollagen type 1 N-terminal propeptide (PINP) compared with patients with no prior tamoxifen. There were no significant differences in bone markers between AIs at any time. By 6 months, significant increases were seen in PINP, C-terminal telopeptides (CTX), bone specific alkaline phosphatise (ALP), and urinary N-terminal telopeptides (NTX). Patients with prior tamoxifen had significantly greater increases than patients with no prior tamoxifen. Patients treated with 3 months of tamoxifen following 6 months of an AI showed a significant decrease in markers of bone resorption, serum CTX and urinary NTX. In conclusion, AI-induced bone turnover increases over time. Anastrozole and letrozole produce similar effects on bone metabolism and turnover. Stopping tamoxifen therapy and starting AIs results in a significantly greater increase in bone turnover compared with commencing AIs in tamoxifen-naïve patients. Patients given tamoxifen following AI therapy showed a decrease in markers of bone resorption.

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

Access this article

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

Similar content being viewed by others

References

  1. Howell A, Cuzick J, Baum M, ATAC Trialists’ Group et al (2005) Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365:60–62

    Article  CAS  PubMed  Google Scholar 

  2. Thurlimann B, Keshaviah A, Coates AS, The Breast International Group (BIG) 1–98 Collaborative Group et al (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747–2757

    Article  PubMed  Google Scholar 

  3. Osborne CK (1999) Aromatase inhibitors in relation to other forms of endocrine therapy for breast cancer. Endocr Relat Cancer 6:271–276

    Article  CAS  PubMed  Google Scholar 

  4. Grey AB, Stapleton JP, Evans MC et al (1995) The effect of the antiestrogen tamoxifen on bone mineral density in normal late postmenopausal women. Am J Med 99:636–641

    Article  CAS  PubMed  Google Scholar 

  5. Marttunen MB, Hietanen P, Tiitinen A et al (1998) Comparison of effects of tamoxifen and toremifene on bone biochemistry and bone mineral density in postmenopausal breast cancer patients. J Clin Endocrinol Metab 83:1158–1162

    Article  CAS  PubMed  Google Scholar 

  6. Horwitz KB (1999) Bringing estrogen receptors under control. Breast Cancer Res 1:5–7

    Article  CAS  PubMed  Google Scholar 

  7. McCloskey E, Hannon R, Lakner G et al (2007) Effects of third generation aromatase inhibitors on bone health and other safety parameters: results of an open, randomised, multi-centre study of letrozole, exemestane and anastrozole in healthy postmenopausal women. Eur J Cancer 43:2523–2531

    Article  CAS  PubMed  Google Scholar 

  8. Coombes RC, Kilburn LS, Snowdon CF, Intergroup Exemestane Study et al (2007) Survival and safety of exemestane versus tamoxifen after 2–3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 369:559–570 erratum in: Lancet 369:906

    Article  CAS  PubMed  Google Scholar 

  9. Dixon JM, Renshaw L, Young O et al (2008) Letrozole suppresses plasma estradiol and estrone sulphate more completely than anastrozole in postmenopausal women with breast cancer. J Clin Oncol 26:1671–1676

    Article  CAS  PubMed  Google Scholar 

  10. Riggs BL (2000) Are biochemical markers for bone turnover clinically useful in monitoring therapy in individuals osteoporotic patients? Bone 26:551–552

    Article  CAS  PubMed  Google Scholar 

  11. Dowsett M, Jones A, Johnston SR et al (1995) In vivo measurements of aromatase inhibition by letrozole (CGS 20267) in postmenopausal patients with breast cancer. Clin Cancer Res 1:1511–1515

    CAS  PubMed  Google Scholar 

  12. Geisler J, King N, Dowsett M et al (1996) Influence of anastrozole (Arimidex), a selective, non-steroidal aromatase inhibitor, on in vivo aromatisation and plasma oestrogen levels in postmenopausal women with breast cancer. Br J Cancer 74:1286–1291

    CAS  PubMed  Google Scholar 

  13. Geisler J, Ekse D, Helle H et al (2006) Letrozole suppresses tissue and plasma estradiol, estrone and estrone sulphate more effectively compared to anastrozole. Breast Cancer Res Treat 199(suppl 1):S23–S24 Abstract 103

    Google Scholar 

  14. Reid DM, Doughty J, Eastell R et al (2008) Guidance for the management of breast cancer treatment-induced bone loss: a consensus position statement from a UK Expert Group. Cancer Treat Rev 34(suppl 1):S3–S18

    Article  CAS  PubMed  Google Scholar 

  15. Coates AS, Keshaviah A, Thurlimann B et al (2007) Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1–98. J Clin Oncol 25:486–492

    Article  CAS  PubMed  Google Scholar 

  16. Hillner B, Ingle JN, Rowan T et al (2003) American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21:4042–4045

    Article  CAS  PubMed  Google Scholar 

  17. Brufsky A, Harker WG, Beck JT et al (2007) Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopausal women with early breast cancer. J Clin Oncol 25:829–836

    Article  CAS  PubMed  Google Scholar 

  18. Bundred NJ, Campbell ID, Davidson N et al (2008) Effective inhibition of aromatase inhibitor-associated bone loss by zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: ZO-FAST study results. Cancer 112:1001–1010

    Article  CAS  PubMed  Google Scholar 

  19. Hadji P, Body JJ, Aapro MS et al (2008) Practical guidance for the management of aromatase inhibitor-associated bone loss. Ann Oncol 19:1407–1416

    Article  CAS  PubMed  Google Scholar 

  20. Chang J, Powles TJ, Ashley SE et al (1996) The effect of tamoxifen and hormone replacement therapy on serum cholesterol, bone mineral density and coagulation factors in healthy postmenopausal women participating in a randomised, controlled tamoxifen prevention study. Ann Oncol 7:671–675

    CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  22. Fisher B, Costantino JP, Wickerham DL et al (2005) Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 97:1652–1662

    Article  CAS  PubMed  Google Scholar 

  23. Eastell R, Hannon RA, Cuzick J, on behalf of the ATAC Trialists’ group et al (2006) Effect of an aromatase inhibitor on BMD and bone turnover markers: 2-year results of the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial. J Bone Miner Res 8:1215–1223

    Article  Google Scholar 

  24. Coleman RE, Banks LM, Kilburn LS, on behalf on the Intergroup Exemestane Study (IES) group (2007) Skeletal effects of exemestane on bone-mineral density, bone biomarkers, and fracture incidence in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study: a randomised controlled study. Lancet 8:119–127

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by unrestricted educational grants from Novartis and Astra Zeneca. The authors thank all of the patients who entered this study.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J. Michael Dixon.

Rights and permissions

Reprints and permissions

About this article

Cite this article

McCaig, F.M., Renshaw, L., Williams, L. et al. A study of the effects of the aromatase inhibitors anastrozole and letrozole on bone metabolism in postmenopausal women with estrogen receptor-positive breast cancer. Breast Cancer Res Treat 119, 643–651 (2010). https://doi.org/10.1007/s10549-009-0646-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-009-0646-0

Keywords

Navigation