Aromatase inhibitors and bone loss

Abstract

The aromatase inhibitors (AIs) anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are significantly more effective than the selective estrogen-receptor modulator (SERM) tamoxifen in preventing recurrence in estrogen receptor-positive early breast cancer. Aromatase inhibitors are likely to replace SERMs as first-line adjuvant therapy for many patients. However, AIs are associated with significantly more osteoporotic fractures and greater bone mineral loss. As antiresorptive agents, oral and intravenous bisphosphonates such as alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), pamidronate (Aredia), and zoledronic acid (Zometa) have efficacy in preventing postmenopausal osteoporosis, cancer treatment-related bone loss, or skeletal complications of metastatic disease. Clinical practice guidelines recommend baseline and annual follow-up bone density monitoring for all patients initiating AI therapy. Bisphosphonate therapy should be prescribed for patients with osteoporosis (T score < -2.5) and considered on an individual basis for those with osteopenia (T score < -1). Modifiable lifestyle behaviors including adequate calcium and vitamin D intake, weight-bearing exercise, and smoking cessation should be addressed. Adverse events associated with bisphosphonates include gastrointestinal toxicity, renal toxicity, and osteonecrosis of the jaw. These safety concerns should be balanced with the potential of bisphosphonates to minimize or prevent the debilitating effects of AI-associated bone loss in patients with early, hormone receptor-positive breast cancer.

Figure 1. Mechanism of Action

—Estrogen regulates physiologic bone remodeling by suppressing osteoclast-mediated bone resorption. During aromatase inhibitor–associated or postmenopausal estrogen deficiency, bone resorption and osteoblast-mediated bone formation are imbalanced, leading to net bone loss.

Figure 2. Steroidal and Nonsteroidal Aromatase Inhibitors

—Letrozole and anastrozole are nonsteroidal third-generation aromatase inhibitors. The steroidal aromatase inhibitor exemestane is an analog of androstenedione, the androgenic substrate of aromatase.

Figure 3. Vertebral and Hip Fracture Risk

The risk of both vertebral and hip fracture is exponentially increased with increasing age and decreasing bone mineral density. Adapted from Cummings et al.[16]

Figure 4. Bisphosponate Structure

—Bisphosphonates are structurally related to the mineralized bone matrix component pyrophosphate and belong to two general classes. The more potent nitrogen-containing bisphosphonates possess one or more nitrogen atoms in their variable side chains around the central carbon atom. Adapted from Reszka et al.[38]