Aromatase Inhibitors and Bone Loss: Risks in Perspective

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 loss 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.” 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. 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 shortand long-term effects on health. The aromatase enzyme converts androgens to estrogens and is the principle source of endogenous estrogen in postmenopausal women. 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. In this issue of the Journal of Clinical Oncology, Lonning et al describe the results of a randomized controlled trial of exemestane or placebo-in “low risk” nodenegative, estrogen and/or progesterone receptor–positive postmenopausal women with early-stage breast cancer. 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, “lowrisk” 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. In contrast, ovariectomized rats receiving letrozole or no aromatase inhibitor had significant loss of JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 22 AUGUST 1 2005