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Originally published as JCO Early Release 10.1200/JCO.2005.03.903 on June 27 2005 © 2005 American Society of Clinical Oncology.
Aromatase Inhibitors and Bone Loss: Risks in PerspectiveBreast Medical Oncology, The Ohio State University Medical Center and Comprehensive Cancer Center, Columbus, OH The prevention and treatment of osteoporosis was once the province of primary care providers or endocrinologists. Not any longer. The increasing awareness that cancer treatments are associated with bone loss1 has led the American Society of Clinical Oncology Task Force to conclude that "Oncology professionals, especially medical oncologists, need to take an expanded role in routine and regular assessment of (these) women's bone health."2 That we should concern ourselves with preventing bone loss and fractures in women with breast cancer is a testament to the increasing relevance of survivorship issues. The key to understanding cancer treatment–associated bone loss in women is estrogen. Estrogen has a protective effect on bone via multiple mechanisms; the net effect is to stimulate new bone formation and inhibit bone resorption.3 In estrogen deficiency states, such as natural menopause, chemotherapy-induced ovarian failure, treatment with gonadotropin-releasing hormone agonists, or treatment with aromatase inhibitors, bone resorption predominates and bone loss ensues. For some women, the clinically relevant end point of osteoporosis (or fractures) will subsequently develop due to unmitigated bone loss plus other important individual genetic, lifestyle, and environmental factors. The recognition that aromatase inhibitors are superior to tamoxifen in treating metastatic disease, and more recently also in the adjuvant setting either as initial treatment or after some prior duration of tamoxifen, has led to concerns about their potential short- and long-term effects on health.4 The aromatase enzyme converts androgens to estrogens and is the principle source of endogenous estrogen in postmenopausal women.5 As a class effect, the aromatase inhibitors cause bone loss by lowering the levels of endogenous estrogen. In contrast, tamoxifen has tissue-specific estrogen agonist effects; in the bone of postmenopausal women, tamoxifen acts as a weak estrogen to preserve bone mineral density (BMD) and may decrease fractures.6-8 In this issue of the Journal of Clinical Oncology, Lønning et al describe the results of a randomized controlled trial of exemestane or placebo-in "low risk" node-negative, estrogen and/or progesterone receptor–positive postmenopausal women with early-stage breast cancer.9 The primary end point was not antitumor efficacy, but rather BMD, with secondary end points of lipid levels and markers of bone turnover. These investigators deserve recognition for conducting a trial focused on important potential short-term side effects of exemestane. Importantly, the trial included a placebo group because at the time, "low-risk" women did not receive adjuvant systemic therapy according to National Guidelines in Norway. The inclusion of the placebo gives a clearer picture of the true effects of exemestane on bone and lipids, unconfounded by comparison to tamoxifen as in the other aromatase inhibitor trials. Is exemestane different from the other aromatase inhibitors? Exemestane is a steroidal irreversible inhibitor, structurally related to androstenedione. The major metabolite of exemestane, 17-hydro-exemestane, is androgenic as well, and androgens have protective effects on bone. In contrast, letrozole and anastrazole are nonsteroidal reversible inhibitors devoid of androgenic activity. This leads to a testable hypothesis: the estrogen deficiency (bone losing) properties of aromatase inhibition with exemestane may be offset by the androgenic (bone preserving) properties of the drug. Indeed, strong support for this hypothesis was demonstrated when ovariectomized rats treated with exemestane and 17-hydro-exemestane had significantly increased BMD, increased strength of cortical and trabecular bone, and decreased markers of bone resorption.10 In contrast, ovariectomized rats receiving letrozole or no aromatase inhibitor had significant loss of BMD accompanied by decreases in bone strength and increases in bone resorption makers. However, in the clinic, the Lønning et al trial illustrates that the "bone-losing" properties of exemestane predominate, though the magnitude of the annual bone loss in the lumbar spine is small and nonsignificant, and statistically significant in the femoral neck. As expected, exemestane treatment increased markers of bone resorption, but also increased markers of bone formation, possibly related to the androgen-like activity. By chance or for other unknown reasons, placebo-treated women experienced higher bone loss than expected. This may have contributed to smaller differences in BMD between exemestane and placebo. However, these results are consistent with those of the Intergroup Exemestane Study (IES) trial where the 1-year bone loss and the overall fracture rate were also higher for exemestane-treated women compared with those who were treated with tamoxifen.11,12 Every postmenopausal woman has ongoing bone loss due to aging and estrogen deficiency. Of more relevance than bone loss per se is the identification of those women at risk of subsequent fracture, and estimation of how much exemestane increases the fracture risk. The fracture risk is best predicted by the T-score or the difference in standard deviations (SDs) between the mean BMD for young (ages 25 to 45 years) women and the BMD for the individual woman. For every –0.5 SD decrease in the T-score, the risk of fractures increases, with higher risks with advancing age.13,14 Using the T-scores to characterize the 10-year hip fracture risk, women age 60 or 70 years treated with 2 years of exemestane had a very small absolute increase of approximately 1% over placebo. Supplemental calcium and vitamin D lessens bone loss and is recommended for postmenopausal women.15 Women in the Lønning et al trial did not receive calcium and vitamin D, and the effect of this on the changes in BMD is unknown. The lack of adequate calcium and vitamin D intake is a recognized as problem in healthy populations, and a small retrospective study suggests that among women with early stage breast cancer calcium and vitamin D intake is also very low.16 The Lønning et al trial therefore adds meaningful information about the short-term side effects of exemestane on bone. With respect to lipids, exemestane was associated with small decreases in high-density lipoprotein cholesterol and apolipoprotein A1. The clinical significance of such changes is unknown. Likewise, the important questions of whether bone loss or fracture rates are lower with exemestane than with the other nonsteroidal aromatase inhibitors is unknown. Answers to these questions will be forthcoming from the ongoing National Cancer Institute of Canada/Clinical Trials Support Unit (http://www.ctsu.org) MA-27 trial, which randomizes women to either adjuvant exemestane or anastrazole. Important secondary end points in this trial include the rates of fractures and cardiovascular effects. These secondary end points become even more relevant as large clinical trials with aromatase inhibitors for the prevention of breast cancer are planned.17 Many women with breast cancer will be long-term survivors. Counseling these women to take adequate calcium and vitamin D, to reduce smoking, and to increase physical activity will promote overall health, as well as bone health. All women receiving aromatase inhibitors should also have their BMD periodically measured and receive bisphosphonates according to published guidelines.2,15 Author's Disclosures of Potential Conflicts of Interest The following author or their immediate family members has indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
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5. Smith IE, Dowsett M: Aromatase inhibitors in breast cancer. N Engl J Med 348: 2431-2442, 2003 6. Love RR, Mazess RB, Barden HS, et al: Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 326: 852-856, 1992[Abstract] 7. Powles T, Hickish T, Kanis J, et al: Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol 14: 78-84, 1996[Abstract]
8. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90: 1371-1388, 1998 9. Lønning PE GJ, 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 23:5126-5137, 2005
10. Goss PE, Qi S, Cheung AM, et al: 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, 2004
11. Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350: 1081-1092, 2004 12. Coleman RE BL, Hall E, et al: Intergroup exemestane study: 1 year results of the bone sub-protocol. Breast Cancer Res Treat 88:S35, 2004 (suppl 1, abstr 401)
13. Cummings SR, Bates D, Black DM: Clinical use of bone densitometry: Scientific review. JAMA 288: 1889-1897, 2002 14. Kanis JA, Johnell O, Oden A, et al: Ten year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds. Osteoporos Int 12: 989-995, 2001[CrossRef][Medline] 15. Delmas PD: Treatment of postmenopausal osteoporosis. Lancet 359: 2018-2026, 2002[CrossRef][Medline] 16. Zinamen RS VPC, Goldberg LM: Supplemental calcium and vitamin D intake of women with early stage breast cancer. Breast Cancer Res Treat 88:S150, 2004 (suppl 1; abstr 4006)
17. Goss PE, Strasser-Weippl K: Prevention strategies with aromatase inhibitors. Clin Cancer Res 10: 372S-379S, 2004 Related Article
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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