, Volume 68, Issue 18, pp 2591–2600 | Cite as

Aromatase Inhibitor-Associated Bone Loss

Clinical Considerations
Review Article


Aromatase inhibitors (AIs) are standard treatments for postmenopausal women with estrogen responsive breast cancers. The mechanism of AIs, inhibition of the aromatase enzyme that causes decreases in endogenous estrogens, is responsible for bone loss and increased fractures. Screening and prevention of AI-induced bone loss closely follows the standard recommendations for postmenopausal osteoporosis. Lifestyle changes such as increasing physical activity and weight-bearing exercise, stopping smoking, and taking adequate amounts of daily calcium and vitamin D promote bone and overall health. Bisphosphonates are specific inhibitors of osteoclasts and reduce bone loss in women treated with AIs. The optimal dose administration schedule and duration of bisphosphonate treatment for AI-induced bone loss remains undefined.


Bone Mineral Density Bone Loss Zoledronic Acid Letrozole Denosumab 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



No sources of funding were used to assist in the preparation of this article. The authors have no conflicts of interest that are directly relevant to the content of this review.


  1. 1.
    Winer EP, Hudis C, Burstein HJ, et al. American society of clinical oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report. J Clin Oncol 2004; 23: 619–29PubMedCrossRefGoogle Scholar
  2. 2.
    Goldhirsch A, Wood WC, Gelber RD, et al. Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer. Ann Oncol 2007; 18: 1133–44PubMedCrossRefGoogle Scholar
  3. 3.
    Brueggemeier R. Aromatase, aromatase inhibitors, and breast cancer. Am J Ther 2001; 8: 333–44PubMedCrossRefGoogle Scholar
  4. 4.
    Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med 2003; 348: 2431–42PubMedCrossRefGoogle Scholar
  5. 5.
    Confavreux CB, Fontana A, Guastalla JP, et al. Estrogen-dependent increase in bone turnover and bone loss in postmenopausal women with breast cancer treated with anastrozole: revention with bisphosphonates. Bone 2007; 41: 346–52PubMedCrossRefGoogle Scholar
  6. 6.
    Lindsay R, Cosman F, Nieves J. Estrogen: effects and actions in osteoporosis. Osteoporos Int 1993; 3 Suppl. 1: 150–2CrossRefGoogle Scholar
  7. 7.
    O’Connell MB. Pharmacokinetic and pharmacologic variation between different estrogen products. J Clin Pharmacol 1995; 35 (9 Suppl.): 18–24SGoogle Scholar
  8. 8.
    Reginster JY, Sarlet N, Deroisy R, et al. Minimal levels of serum estradiol prevent postmenopausal bone loss. Calcif Tissue Int 1992; 51: 340–3PubMedCrossRefGoogle Scholar
  9. 9.
    Lindsay R, Hart DM, Aitken JM, et al. Long-term prevention of postmenopausal osteoporosis by oestrogen: evidence for an increased bone mass after delayed onset of oestrogen treatment. Lancet 1976; I: 1038–41CrossRefGoogle Scholar
  10. 10.
    Gnant MFX, Mlineritsch B, Luschin-Ebengreuth G, et al. Zoledronic acid prevents cancer treatment-induced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormone-responsive breast cancer: a report from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol 2007; 25: 820–8PubMedCrossRefGoogle Scholar
  11. 11.
    Shapiro CL, Manola J, Leboff M. Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer. J Clin Oncol 2001; 19: 3306–11PubMedGoogle Scholar
  12. 12.
    Saarto T, Blomqvist C, Valimaki M, et al. Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes rapid bone loss that is reduced by clodronate: a randomized study in premenopausal breast cancer patients. J Clin Oncol 1997; 15: 1341–7PubMedGoogle Scholar
  13. 13.
    Eastell R, Adams JE, Coleman RE, et al. Effect of anastrozole on bone mineral density: 5-year results from the Anastrozole, Tamoxifen, Alone or in Combination Trial 18233230. J Clin Oncol 2008; 26: 1051–7PubMedCrossRefGoogle Scholar
  14. 14.
    Gnant MF, Mlineritsch B, Luschin-Ebengreuth G, et al. Zoledronic acid prevents cancer treatment-induced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormone-responsive breast cancer: a report from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol 2007; 25: 820–8PubMedCrossRefGoogle Scholar
  15. 15.
    Warming L, Hassager C, Christiansen C. Changes in bone mineral density with age in men and women: a longitudinal study. Osteoporos Int 2002; 13: 105–12PubMedCrossRefGoogle Scholar
  16. 16.
    Nelson HD, Humphrey LL, Nygren P, et al. Postmenopausal hormone replacement therapy: scientific review. JAMA 2002; 288: 872–81PubMedCrossRefGoogle Scholar
  17. 17.
    Eichner SF, Lloyd KB, Timpe EM. Comparing therapies for postmenopausal osteoporosis prevention and treatment. Ann Pharmacother 2003; 37: 711–24PubMedCrossRefGoogle Scholar
  18. 18.
    Love RR, Mazess RB, Barden HS, et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer [see comments]. N Engl J Med 1992; 326: 852–6PubMedCrossRefGoogle Scholar
  19. 19.
    Felsenberg D, Boonen S. The bone quality framework: determinants of bone strength and their interrelationships, and implications for osteoporosis management. Clin Ther 2005; 27: 1–11PubMedCrossRefGoogle Scholar
  20. 20.
    Davison KS, Siminoski K, Adachi JD, et al. Bone strength: the whole is greater than the sum of its parts. Semin Arthritis Rheum 2006; 36: 22–31PubMedCrossRefGoogle Scholar
  21. 21.
    Manolagas SC, Jilka RL. Bone marrow, cytokines, and bone remodeling: emerging insights into the pathophysiology of osteoporosis. N Engl J Med 1995; 332: 305–11PubMedCrossRefGoogle Scholar
  22. 22.
    Karsenty G, Ducy P. The hypothalamic control of bone mass, implication for the treatment of osteoporosis. Ann Endocrinol (Paris) 2006; 67: 123CrossRefGoogle Scholar
  23. 23.
    Ramaswamy B, Shapiro CL. Osteopenia and osteoporosis in women with breast cancer. Semin Oncol 2003; 30: 763–75PubMedCrossRefGoogle Scholar
  24. 24.
    Kearns AE, Khosla S, Kostenuik P. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev 2008; 29(2): 155–92PubMedCrossRefGoogle Scholar
  25. 25.
    Boyce BF, Xing L. The RANKL/RANK/OPG pathway. Curr Osteoporos Rep 2007; 5: 98–104PubMedCrossRefGoogle Scholar
  26. 26.
    Dougall WC, Chaisson M. The RANK/RANKL/OPG triad in cancer-induced bone diseases. Cancer Metastasis Rev 2006; 25: 541–9PubMedCrossRefGoogle Scholar
  27. 27.
    Hofbauer LC, Neubauer A, Heufelder AE. Receptor activator of nuclear factor-kappaB ligand and osteoprotegerin: potential implications for the pathogenesis and treatment of malignant bone diseases. Cancer 2001; 92: 460–70PubMedCrossRefGoogle Scholar
  28. 28.
    Kostenuik PJ. Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength. Curr Opin Pharmacol 2005; 5: 618–25PubMedCrossRefGoogle Scholar
  29. 29.
    Weitzmann MN, Pacifici R. Estrogen deficiency and bone loss: an inflammatory tale. J Clin Invest 2006; 116: 1186–94PubMedCrossRefGoogle Scholar
  30. 30.
    Geisler J, Lonning PE. Endocrine effects of aromatase inhibitors and inactivators in vivo: review of data and method limitations. J Steroid Biochem Mol Biol 2005; 95: 75–81PubMedCrossRefGoogle Scholar
  31. 31.
    Simpson ER, Dowsett M. Aromatase and its inhibitors: significance for breast cancer therapy. Recent Prog Horm Res 2002; 57: 317–38PubMedCrossRefGoogle Scholar
  32. 32.
    Dixon JM. Exemestane: a potent irreversible aromatase inactivator and a promising advance in breast cancer treatment. Expert Rev Anticancer Ther 2002; 2: 267–75PubMedCrossRefGoogle Scholar
  33. 33.
    Lonning P. Pharmacology and clinical experience with exemestane. Expert Opin Investig Drugs 2000; 9: 1897–905PubMedCrossRefGoogle Scholar
  34. 34.
    Geisler J. Breast cancer tissue estrogens and their manipulation with aromatase inhibitors and inactivators. J Steroid Biochem Mol Biol 2003; 86: 245–53PubMedCrossRefGoogle Scholar
  35. 35.
    Geisler J, Haynes B, Anker G, et al. Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study. J Clin Oncol 2002; 20: 751–7PubMedCrossRefGoogle Scholar
  36. 36.
    Lamb HM, Adkins JC. Letrozole: a review of its use in postmen-opausal women with advanced breast cancer. Drugs 1998; 56: 1125–40PubMedCrossRefGoogle Scholar
  37. 37.
    Wiseman LR, Adkins JC. Anastrozole: a review of its use in the management of postmenopausal women with advanced breast cancer. Drugs Aging 1998; 13: 321–32PubMedCrossRefGoogle Scholar
  38. 38.
    Goss PE, Qi S, Josse RG, et al. The steroidal aromatase inhibitor exemestane prevents bone loss in ovariectomized rats. Bone 2004; 34: 384–92PubMedCrossRefGoogle Scholar
  39. 39.
    Lonning PE, Geisler J, Krag LE, et al. 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 2005; 23(22): 5126–37PubMedCrossRefGoogle Scholar
  40. 40.
    National Cancer Institute. Phase III randomized adjuvant study of exemestane versus anastrozole in postmenopausal women with receptor-positive primary breast cancer [online]. Available from URL: [Accessed 2008 Oct 13]
  41. 41.
    Khan MN, Khan AA. Cancer treatment-related bone loss: a review and synthesis of the literature. Curr Oncol 2008; 15 Suppl. 1: S30–40PubMedCrossRefGoogle Scholar
  42. 42.
    Chowdhury S, Pickering LM, Ellis PA. Adjuvant aromatase inhibitors and bone health. J Br Menopause Soc 2006; 12: 97–103PubMedCrossRefGoogle Scholar
  43. 43.
    McCloskey E. Effects of third-generation aromatase inhibitors on bone. Eur J Cancer 2006; 42: 1044–51PubMedCrossRefGoogle Scholar
  44. 44.
    Perez EA. Safety of aromatase inhibitors in the adjuvant setting. Breast Cancer Res Treat 2007; 105 Suppl. 1: 75–89CrossRefGoogle Scholar
  45. 45.
    Body JJ, Bergmann P, Boonen S, et al. Management of cancer treatment-induced bone loss in early breast and prostate cancer: a consensus paper of the Belgian Bone Club. Osteoporos Int 2007; 18: 1439–50PubMedCrossRefGoogle Scholar
  46. 46.
    Eastell R. Aromatase inhibitors and bone. J Steroid Biochem Mol Biol 2007; 106: 157–61PubMedCrossRefGoogle Scholar
  47. 47.
    Coates AS, Keshaviah A, Thurlimann B, et al. 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 2007; 25: 486–92PubMedCrossRefGoogle Scholar
  48. 48.
    Coombes RC, Kilburn LS, Snowdon CF, et al. Survival and safety of exemestane versus tamoxifen after 2–3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 2007; 369: 559–70PubMedCrossRefGoogle Scholar
  49. 49.
    Forbes JF, Cuzick J, Buzdar A, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 2008; 9: 45–53PubMedCrossRefGoogle Scholar
  50. 50.
    Goss PE, Ingle JN, Martino S, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA. 17. J Natl Cancer Inst 2005; 97: 1262–71CrossRefGoogle Scholar
  51. 51.
    Jakesz R, Jonat W, Gnant M, et al. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 2005; 366: 455–62PubMedCrossRefGoogle Scholar
  52. 52.
    Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006; 354: 669–83PubMedCrossRefGoogle Scholar
  53. 53.
    Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA 2005; 293: 2257–64PubMedCrossRefGoogle Scholar
  54. 54.
    Brown JP, Josse RG. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ 2002; 167 (10 Suppl.): S1–34PubMedGoogle Scholar
  55. 55.
    Hillner BE, Ingle JN, Chlebowski RT, et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 2003; 21: 4042–57PubMedCrossRefGoogle Scholar
  56. 56.
    Michaud LB, Goodin S. Cancer-treatment-induced bone loss, part 2. Am J Health Syst Pharm 2006; 63: 534–46PubMedCrossRefGoogle Scholar
  57. 57.
    Coleman RE, Banks LM, Girgis SI, et al. 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 2007; 8: 119–27PubMedCrossRefGoogle Scholar
  58. 58.
    Perez EA, Josse RG, Pritchard KI, et al. Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: a companion study to NCIC CTG MA. 17. J Clin Oncol 2006; 24: 3629–35CrossRefGoogle Scholar
  59. 59.
    Jones SE, Cantrell J, Vukelja S, et al. The effects of tamoxifen (T) or exemestane (E) on bone mineral density (BMD) after 1 year of adjuvant treatment of postmenopausal women with early breast cancer [abstract no. 610]. J Clin Oncol 2005; 23: 31SGoogle Scholar
  60. 60.
    Eastell R, Hannon RA, Cuzick J, et al. Effect of an aromatase inhibitor on bmd and bone turnover markers: 2-year results of the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial (18233230). J Bone Miner Res 2006; 21: 1215–23PubMedCrossRefGoogle Scholar
  61. 61.
    Khosla S, Riggs BL. Pathophysiology of age-related bone loss and osteoporosis. Endocrinol Metab Clin North Am 2005; 34: 1015–30, xiPubMedCrossRefGoogle Scholar
  62. 62.
    Mazzuoli G, Acca M, Pisani D, et al. Annual skeletal balance and metabolic bone marker changes in healthy early postmenopausal women: results of a prospective study. Bone 2000; 26: 381–6PubMedCrossRefGoogle Scholar
  63. 63.
    Seeman E. Pathogenesis of bone fragility in women and men. Lancet 2002; 359: 1841–50PubMedCrossRefGoogle Scholar
  64. 64.
    Scifert-Klauss V, Link T, Heumann C, et al. Influence of pattern of menopausal transition on the amount of trabecular bone loss: results from a 6-year prospective longitudinal study. Maturitas 2006; 55: 317–24CrossRefGoogle Scholar
  65. 65.
    Anonymous. Osteoporosis prevention, diagnosis, and therapy. NIH Consensus Statement 2000; 17: 1–45Google Scholar
  66. 66.
    Kanis JA. Diagnosis of osteoporosis and assessment of fracture risk. Lancet 2002; 359: 1929–36PubMedCrossRefGoogle Scholar
  67. 67.
    Kanis JA, Burlet N, Cooper C, et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 2008; 19(4): 399–428PubMedCrossRefGoogle Scholar
  68. 68.
    Kanis JA, McCloskey EV, Johansson H, et al. A reference standard for the description of osteoporosis. Bone 2008; 42: 467–75PubMedCrossRefGoogle Scholar
  69. 69.
    Kanis JA, Brazier JE, Stevenson M, et al. Treatment of established osteoporosis: a systematic review and cost-utility analysis. Health Technol Assess 2002; 6: 1–146PubMedGoogle Scholar
  70. 70.
    Cummings SR, Nevitt MC, Browner WS, et al. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med 1995; 332: 767–73Google Scholar
  71. 71.
    Cummings SR, Bates D, Black DM. Clinical use of bone densitometry: scientific review. JAMA 2002; 288: 1889–97PubMedCrossRefGoogle Scholar
  72. 72.
    Brufsky A, Harker WG, Beck JT, et al. Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopausal women with early breast cancer. J Clin Oncol 2007; 25: 829–36PubMedCrossRefGoogle Scholar
  73. 73.
    Brufsky A, Bosserman L, Caradonna R, et al. The effect of zoledronic acid on aromatase inhibitor-associated bone loss in postmenopausal woemn with early breast cancer receiving adjuvant letrozole: the Z-FAST study 36-month follow-up [abstract no. 27]. Breast Cancer Res Treat 2007; 106 Suppl. 1: S8Google Scholar
  74. 74.
    NIH Consensus Development Panel on Osteoporosis Prevention DaT. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001; 285: 785–95CrossRefGoogle Scholar
  75. 75.
    Lester JE, Dodwell D, Horsman JM, et al. Current management of treatment-induced bone loss in women with breast cancer treated in the United Kingdom. Br J Cancer 2006; 94: 30–5PubMedCrossRefGoogle Scholar
  76. 76.
    Schwartz AL, Winters-Stone K, Gallucci B. Exercise effects on bone mineral density in women with breast cancer receiving adjuvant chemotherapy. Oncol Nurs Forum 2007; 34: 627–33PubMedCrossRefGoogle Scholar
  77. 77.
    Demark-Wahnefried W, Aziz NM, Rowland JH, et al. Riding the crest of the teachable moment: promoting long-term health after the diagnosis of cancer. J Clin Oncol 2005; 23(24): 5814–30PubMedCrossRefGoogle Scholar
  78. 78.
    Demark-Wahnefried W, Pinto BM, Gritz ER. Promoting health and physical function among cancer survivors: potential for prevention and questions that remain. J Clin Oncol 2006; 24: 5125–31PubMedCrossRefGoogle Scholar
  79. 79.
    Russell RG, Watts NB, Ebetino FH, et al. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int 2008; 19: 733–9PubMedCrossRefGoogle Scholar
  80. 80.
    Bundred NJ, Campbell ID, Davidson N, et al. 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 2008; 112(5): 1001–10PubMedCrossRefGoogle Scholar
  81. 81.
    Aapro M. Improving bone health in patients with early breast cancer by adding bisphosphonates to letrozole: the Z-ZOEZO-FAST program. Breast 2006; 15 Suppl. 1: S30–40PubMedCrossRefGoogle Scholar
  82. 82.
    Von Poznak C, Hannon RA, Clack G, et al. The SABRE (Study of Anastrazole with the Bisphosphonate RisedrontE) study: 12-month analysis [abstract no. 502]. Breast Cancer Res Treat 2007; 106: S37Google Scholar
  83. 83.
    Bamias A, Kastritis E, Bamia C, et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 2005; 23: 8580–7PubMedCrossRefGoogle Scholar
  84. 84.
    Diel IJ, Bergner R, Grotz KA. Adverse effects of bisphosphonates: current issues. J Support Oncol 2007; 5: 475–82PubMedGoogle Scholar
  85. 85.
    Mehrotra B. Safety profile of intravenous bisphosphonates. Semin Oncol 2007; 34 (6 Suppl. 4): S24–7PubMedCrossRefGoogle Scholar
  86. 86.
    Pazianas M, Blumentals WA, Miller PD. Lack of association between oral bisphosphonates and osteonecrosis using jaw surgery as a surrogate marker. Osteoporos Int 2008; 19: 773–9PubMedCrossRefGoogle Scholar
  87. 87.
    American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2007; 65: 369–76CrossRefGoogle Scholar
  88. 88.
    Weitzman R, Sauter N, Eriksen EF, et al. Critical review: updated recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in cancer patients. Crit Rev Oncol Hematol 2006; 62: 148–52CrossRefGoogle Scholar
  89. 89.
    Pazianas M, Miller P, Blumentals WA, et al. A review of the literature on osteonecrosis of the jaw in patients with osteoporosis treated with oral bisphosphonates: prevalence, risk factors, and clinical characteristics. Clin Ther 2007; 29: 1548–58PubMedCrossRefGoogle Scholar
  90. 90.
    Bobba RS, Beattie K, Parkinson B, et al. Tolerability of different dosing regimens of bisphosphonates for the treatment of osteoporosis and malignant bone disease. Drug Saf 2006; 29: 1133–52PubMedCrossRefGoogle Scholar
  91. 91.
    Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007; 356: 1809–22PubMedCrossRefGoogle Scholar
  92. 92.
    Schwarz EM, Ritchlin CT. Clinical development of anti-RANKL therapy. Arthritis Res Ther 2007; 9 Suppl. 1: S7PubMedCrossRefGoogle Scholar
  93. 93.
    Ellis G, Bone H, Chelebowski R, et al. A phase study of the effect of denosumab therapy on bone mineral density in women receiving aroamatase inhibitors for non metastatic breast cancer [abstract no. 47]. Breast Cancer Res Treat 2007; 101: S1CrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  1. 1.The Comprehensive Breast Health Services, Arthur G. James Cancer Hospital and Richard J. Solve Research InstituteThe Ohio State University Medical CenterColumbusUSA

Personalised recommendations