Aromatase Inhibitor–Associated Musculoskeletal Symptoms: Etiology and Strategies for Management

In the United States, approximately 180,000 women are diagnosed with breast cancer annually.[1] The incidence of breast cancer increases with advancing age; approximately 75% of patients are postmenopausal at diagnosis.[2] Hormone receptors (HR) are overexpressed on 80% of breast cancer tumors in postmenopausal women.[3] Therefore, more than 100,000 postmenopausal women who are diagnosed with breast cancer each year in the United States are potential candidates for antiendocrine breast cancer therapy with an aromatase inhibitor (AI), either in the front-line setting or after 2 to 5 years of tamoxifen(Drug information on tamoxifen) therapy.

Survival of patients with early-stage HR-positive breast cancer has significantly improved during the past few decades, in part because of the introduction of adjuvant endocrine therapy with agents such as tamoxifen.[4,5] More recently, large randomized clinical trials of the three third-generation AIs in routine clinical use—anastrozole (Arimidex), letrozole(Drug information on letrozole) (Femara), and exemestane(Drug information on exemestane) (Aromasin)—have demonstrated improvements in disease-free and overall survival with the use of AI therapy upfront or in sequence with tamoxifen in postmenopausal women with early-stage HR-positive breast cancer.[6]

In cross-study comparisons, the three AIs appear to have both similar efficacy (Table 1) and similar toxicity profiles. The primary toxicities include decreases in bone mineral density, increases in risk of fracture, and musculoskeletal symptoms. This review will focus on AI-associated musculoskeletal toxicity, including typical symptoms, potential etiologies, and strategies for management of the side effects.

Aromatase Inhibitor Efficacy and Safety

The aromatase (CYP19) enzyme catalyzes the final step in the conversion of androgens to estrogens.[6] The nonsteroidal AIs anastrozole(Drug information on anastrozole) and letrozole competitively inhibit aromatase, whereas the steroidal AI exemestane irreversibly inhibits the enzyme. This inhibition of aromatase in postmenopausal women leads to reductions of serum estradiol(Drug information on estradiol) concentrations significantly below postmenopausal levels, which decreases the likelihood of breast cancer recurrence in women with HR-positive tumors. AIs are ineffective in women with functional ovaries because of their inability to block ovarian production of estrogen.[7]

The AIs have been evaluated in numerous large randomized controlled trials for early-stage HR-positive breast cancer in multiple settings: upfront in place of tamoxifen, following 2 to 3 years of tamoxifen (switching strategy), or after completion of 5 years of tamoxifen therapy (extended strategy).[6,8-15] As shown in Table 1, these and other randomized studies have consistently shown a small but statistically significant improvement in disease-free survival with AI therapy compared to tamoxifen or placebo. To date, no studies have demonstrated an overall survival advantage in an intent-to-treat analysis, and only two studies have demonstrated an overall survival advantage in selected subgroups (Table 1).

Overall, results of these clinical trials have demonstrated a favorable safety profile for the AIs compared to tamoxifen.[16] The serious toxicities caused by tamoxifen, notably thromboembolic disease and endometrial cancer, were not increased by AI therapy. However, the AIs were noted to cause a loss of bone mineral density, with a concomitant increased risk of fractures. Across the large randomized controlled studies, between 20% and 36% of AI-treated patients also developed arthralgias, which was statistically significantly higher than the incidence in either tamoxifen- or placebo-treated patients (Table 2).[11,14,17,18] However, the clinical impact of these AI-associated musculoskeletal symptoms (AIMSS) was not fully appreciated since few subjects in the large clinical trials were reported to discontinue therapy as a direct result of this toxicity.

AI-Associated Arthralgias

As the clinical importance of AIMSS has become more evident, a number of reports have characterized the variety of symptoms and syndromes that develop in AI-treated patients.

ATAC Trial

A comprehensive analysis of musculoskeletal data from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial revealed that 36.5% of women without preexisting joint symptoms developed arthralgias when treated with anastrozole, compared to 30.9% of women treated with tamoxifen (P < .001).[19] The majority of symptoms that developed were mild or moderate, and there was no difference in the incidence of severe arthralgias between the two treatment groups. Patients were more likely to develop pain during the first few years of treatment, although the risk persisted throughout the 5-year duration of the trial. Further description of the symptoms that developed (ie, location and character of symptoms, diagnostic evaluation by a trained musculoskeletal assessor) was not reported in this analysis.

Columbia University Study

Researchers at Columbia University reported the results of a cross-sectional study of 200 women on adjuvant AI therapy.[20] In their cohort, 47% reported AI-related joint pain and 44% reported joint stiffness. The arthralgias were equally divided between new onset of pain and exacerbation of preexisting symptoms, whereas the majority of joint stiffness was new since initiation of AI therapy. The most common sites of pain and stiffness reported by subjects in this study were the hands, knees, and back. Two-thirds of patients self-rated their pain as moderate or severe, which was greater than what was reported in the ATAC trial.