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Evaluation and management of aromatase inhibitor-induced bone loss

Charles L Shapiro, MD
Shubham Pant, MD
Section Editor
Clifford J Rosen, MD
Deputy Editor
Jean E Mulder, MD


Aromatase inhibitors (AIs) are an important component of adjuvant endocrine therapy in postmenopausal women with estrogen receptor-positive breast cancer. AIs inhibit the cytochrome P450 CYP-19 enzyme responsible for the peripheral conversion of androgens to estrogens [1,2]. Treatment with AIs, therefore, results in bone loss due to estrogen deficiency [3]. As more women are exposed to AIs, it is important to understand their adverse effects on the skeleton. The evaluation and management of bone loss associated with the use of AIs are reviewed here. The role of AIs as adjuvant therapy for breast cancer is discussed elsewhere. (See "Adjuvant endocrine therapy for non-metastatic, hormone receptor-positive breast cancer".)


The central role of estrogen deficiency in the pathogenesis of osteoporosis in postmenopausal women has been recognized for many years. Estrogen inhibits bone resorption, and after menopause, estrogen deficiency results in increased bone resorption and rapid bone loss. The mechanisms by which estrogen regulates bone remodeling are not fully established. However, estrogen is thought to affect osteoclastogenesis and osteoclast function through its effects on local cytokines and growth factors (eg, produced by either bone cells or adjacent marrow cells). This topic is reviewed separately. (See "Pathogenesis of osteoporosis", section on 'Sex steroid deficiency'.)

AI-induced estrogen deficiency — Although the primary source of estrogen in premenopausal women is the ovaries, the primary source in postmenopausal women is the adrenal gland, where aromatase converts adrenal androgens to estrogens. Aromatase inhibitors (AIs) prevent conversion of androgens to estrogens. In postmenopausal women, AIs cause relatively rapid decreases in circulating estrogen [4,5]. (See "Overview of androgen deficiency and therapy in women".)

The AIs are divided into steroidal inactivators (exemestane) and nonsteroidal inhibitors (letrozole, anastrozole). Exemestane is a steroidal analogue of androstenedione and binds irreversibly to aromatase [6,7]. Nonsteroidal inhibitors, like letrozole or anastrozole, bind reversibly to the heme group of the enzyme by way of a basic nitrogen atom. At clinical doses, these third-generation AIs are successful in inhibiting greater than 97 percent of aromatase activity in vivo [4,8,9]. The half-life of these compounds varies from 27 hours for exemestane to 48 hours for letrozole and anastrozole [7,10,11].

In vivo animal studies suggest that exemestane may be more bone sparing than letrozole, owing to its androgenic structure [12,13]. However, there are no human trials showing a differential effect of the individual AIs on bone. The MA-27 trial compared exemestane and anastrozole as adjuvant therapy in postmenopausal women [14]. Clinical fracture data were collected as adverse events. Although self-reported new diagnoses of osteoporosis were significantly less frequent on exemestane than anastrozole, there was no difference in the number of new clinical fragility fractures between the two groups (4 percent in each group).

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Literature review current through: Nov 2017. | This topic last updated: Mar 07, 2017.
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