The effect of exemestane and tamoxifen on bone health within the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial: a meta-analysis of the US, German, Netherlands, and Belgium sub-studies

Abstract

Purpose

We performed a meta-analysis of three sub-studies of the randomized Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial to determine the effects of exemestane and tamoxifen on bone health.

Methods

Patients received exemestane or tamoxifen as adjuvant therapy for hormone receptor–positive breast cancer. Bone mineral density (BMD) was assessed at baseline and after 12 and 24 months of treatment. Bone turnover markers were also measured.

Results

Patients receiving tamoxifen showed a mean increase from baseline in lumbar spine BMD of 1.2% at month 12 and 0.2% at month 24. Patients receiving exemestane showed a mean decrease from baseline of 2.6% after 12 months and 3.5% after 24 months. There were significant differences in the changes in lumbar spine BMD between treatment groups (P < 0.0001 at both time points). Changes in BMD from baseline at the total hip were also significantly different between exemestane and tamoxifen (P < 0.05 at both time points). Bone turnover markers decreased from baseline with tamoxifen and increased with exemestane.

Conclusions

Exemestane resulted in decreases in BMD and increases in bone turnover markers. BMD increased and bone turnover markers decreased with tamoxifen.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. 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

    PubMed  Article  CAS  Google Scholar 

  2. Coleman RE, Banks LM, Girgis SI et al (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 (IES): a randomised controlled study. Lancet Oncol 8:119–127

    PubMed  Article  CAS  Google Scholar 

  3. Coleman RE, Banks LM, Girgis SI et al (2008a) Reversal of skeletal effects of endocrine treatments in the intergroup exemestane study. Poster presentation at San Antonio Breast Cancer Symposium (SABCS), San Antonio, Texas, USA, 10–14 December

  4. Coleman RE, Bolten WW, Lansdown M et al (2008b) Aromatase inhibitor-induced arthralgia: clinical experience and treatment recommendations. Cancer Treat Rev 34:275–282

    PubMed  Article  CAS  Google Scholar 

  5. Coombes RC, Hall E, Gibson LJ et al (2004) A randomized trial of exemestane after 2–3 years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081–1092

    PubMed  Article  CAS  Google Scholar 

  6. Coombes RC, Kilburn LS, Snowdon CF 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

    PubMed  Article  CAS  Google Scholar 

  7. Coombes RC, Kilburn LS, Beare S et al (2009) Survival and safety post study treatment completion: an updated analysis of the intergroup exemestane study (IES)—submitted on behalf of the IES investigators. Oral presentation at the joint ECCO 15-ESMO 34 meeting, Berlin, Germany, 20–24 Sept 2009

  8. Eastell R, Adams JE, Coleman RE et al (2008) Effect of anastrozole on bone mineral density: 5 year results from the anastrozole, tamoxifen, alone or in combination trial 18233230. J Clin Oncol 26:1051–1057

    PubMed  Article  CAS  Google Scholar 

  9. Forbes JF, Cuzick J, Buzdar A et al (2008) Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100 month analysis of the ATAC trial. Lancet Oncol 9:45–53

    PubMed  Article  Google Scholar 

  10. Frenkel B, Hong A, Baniwal SK et al (2010) Regulation of adult bone turnover by sex steroids. J Cell Physiol 224:305–310

    PubMed  Article  CAS  Google Scholar 

  11. Goldhirsch A, Ingle JN, Gelber RD et al (2009) Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009. Ann Oncol 20:1319–1329

    PubMed  Article  CAS  Google Scholar 

  12. Goss PE, Qi S, Cheung AM et al (2004) Effects of the steroidal aromatase inhibitor exemestane and the nonsteroidal aromatase inhibitor letrozole on bone and lipid metabolism in ovariectomized rats. Clin Cancer Res 10:5717–5723

    PubMed  Article  CAS  Google Scholar 

  13. Goss PE, Hadji P, Subar M et al (2007) Effects of steroidal and nonsteroidal aromatase inhibitors on markers of bone turnover in healthy postmenopausal women. Breast Cancer Res 9:R52

    PubMed  Article  Google Scholar 

  14. Hadji P (2007) Aromatase inhibitor-associated bone loss in breast cancer. US Oncolo Dis 1:18–21

    Google Scholar 

  15. Hadji P (2008a) Aromatase inhibitor-associated bone loss in breast cancer patients is distinct from postmenopausal osteoporosis. Crit Rev Oncol Hematol 69:73–82

    PubMed  Article  Google Scholar 

  16. Hadji P (2008b) Menopausal symptoms and adjuvant therapy-associated adverse events. Endocr Relat Cancer 15:73–90

    PubMed  Article  CAS  Google Scholar 

  17. Hadji P, Bundred N (2007) Reducing the risk of cancer treatment-associated bone loss in patients with breast cancer. Semin Oncol 34:S4–S10

    PubMed  Article  CAS  Google Scholar 

  18. 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

    PubMed  Article  CAS  Google Scholar 

  19. Hadji P, Ziller M, Kieback DG et al (2009a) Effects of exemestane and tamoxifen on bone health within the tamoxifen exemestane adjuvant multicentre (TEAM) trial: results of a German, 12 month, prospective, randomised sub-study. Ann Oncol 20:203–207

    Article  Google Scholar 

  20. Hadji P, Ziller M, Kieback DG et al (2009b) The effect of exemestane or tamoxifen on markers of bone turnover: results of a German sub-study of the tamoxifen exemestane adjuvant multicentre (TEAM) trial. Breast 18:159–164

    PubMed  Article  CAS  Google Scholar 

  21. Howell A, Cuzick J, Baum M 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

    PubMed  Article  CAS  Google Scholar 

  22. Hozumi Y, Aihara T, Suemasu K et al (2010) The effect of exemestane and anastrozole on bone mineral density and bone turnover markers in postmenopausal early breast cancer patients: final results of 3 years after randomization of N-SAS (national surgical adjuvant study) BC04, the TEAM Japan sub-study. Poster presentation at the European Breast Cancer Conference, Barcelona, Spain, 24–27 March

  23. Jones S, Stokoes C, Sborov M (2008a) The effect of tamoxifen or exemestane on bone mineral density during the first 2 years of adjuvant treatment of postmenopausal women with early breast cancer. Clin Breast Cancer 8:527–532

    PubMed  Article  CAS  Google Scholar 

  24. Jones SE, Seynaeve C, Hasenburg A et al (2008b) Results of the first planned analysis of the TEAM (tamoxifen exemestane adjuvant multinational) prospective randomized phase III trial in hormone sensitive postmenopausal early breast cancer. Oral presentation at San Antonio breast cancer symposium (SABCS), San Antonio, Texas, USA, 10–14 December

  25. Lönning PE, Geisler J, Krag LE et al (2005) Effects of exemestane administered for 2 years versus placebo on bone mineral density, bone biomarkers, and plasma lipids in patients with surgically resected early breast cancer. J Clin Oncol 23:5126–5137

    PubMed  Article  Google Scholar 

  26. Love RR, Mazess RB, Barden HS et al (1992) Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 326:852–856

    PubMed  Article  CAS  Google Scholar 

  27. McCloskey EV, Hannon RA, 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

    PubMed  Article  CAS  Google Scholar 

  28. Miller WR, Bartlett J, Brodie AM et al (2008) Aromatase inhibitors: are there differences between steroidal and nonsteroidal aromatase inhibitors and do they matter? Oncologist 13:829–837

    PubMed  Article  CAS  Google Scholar 

  29. National Comprehensive Cancer Network (2009) NCCN clinical practice guidelines in oncology: breast cancer V.1.2009. http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf

  30. Rabaglio M, Sun Z, Price KN et al (2009) Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1–98 trial. Ann Oncol 20:1489–1498

    PubMed  Article  CAS  Google Scholar 

  31. Rea DW, Hasenburg A, Seynaeve C et al (2009) Five years of exemestane as initial therapy compared to 5 years of tamoxifen followed by exemestane: The TEAM trial, a prospective, randomized, phase III trial in postmenopausal women with hormone-sensitive early breast cancer. Oral presentation at San Antonio Breast Cancer Symposium (SABCS), San Antonio, Texas, USA, 10–13 December

  32. van Nes JGH, Papapoulos SE, Braun JJ et al (2008) Effect of exemestane on bone turnover markers and bone mineral density (BMD): 2 year results of the Dutch/Belgian Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial. Poster presentation at San Antonio breast cancer symposium (SABCS), San Antonio, Texas, USA, 10–14 December

  33. van Nes JGH, Seynaeve C, Jones S et al (2010) Variations in loco regional therapy in postmenopausal patients with early breast cancer treated in different countries. Br J Surg 97:671–679

    PubMed  Article  Google Scholar 

Download references

Acknowledgments

The authors would like to acknowledge Dr Luc Dirix for his help with the Belgian data. Editorial assistance for this paper was provided by Caroline Masterman at ACUMED (Tytherington, UK) and was funded by Pfizer, Inc. This work was supported by a scientific research grant from Pfizer, Inc [grant number EXEAPO-0028-119].

Conflict of interest

Dr Hadji has received unrestricted educational grants, scientific research grants, and lecture fees from Pfizer, Inc. Dr Hasenburg has received honoraria for lectures from Pfizer, Inc. Dr Jones has received honoraria as a member of the speakers bureau for Pfizer, Inc. Dr Ziller has received support for travel to meetings for the study. Dr Menschik is a Pfizer employee and holds Pfizer stock. Dr Asmar, Dr van de Velde, Dr van Nes, Dr Nortier, and Mr Kuck have no conflicts of interest beyond elements of the Pfizer funding of the study noted in the Acknowledgements. The corresponding author had full access to all data and final responsibility for the decision to submit for publication.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Peyman Hadji.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hadji, P., Asmar, L., van Nes, J.G.H. et al. The effect of exemestane and tamoxifen on bone health within the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial: a meta-analysis of the US, German, Netherlands, and Belgium sub-studies. J Cancer Res Clin Oncol 137, 1015–1025 (2011). https://doi.org/10.1007/s00432-010-0964-y

Download citation

Keywords

  • Aromatase inhibitor
  • Early breast cancer
  • Exemestane
  • Tamoxifen
  • Bone mineral density