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.
Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center Torrance, California
In their article, Drs. Perez and Weilbecher provide an informed, balanced, conprehensive review of aromatase inhibitors and bone loss with considerable emphasis on the randomized adjuvant trials comparing aromatase inhibitors to tamoxifen. They suggest that current guidelines for management of bone health related to aromatase inhibitor use may be considered "conservative," and relate the influence of tamoxifen and aromatase inhibitors on bone health as an important component in the individualized decision-making process for breast cancer patients. While in general agreement, available and emerging evidence suggests the magnitude of concern regarding aromatase inhibitor use and bone loss can be mitigated.[1,2]
Fracture incidence has been consistently higher in women receiving aromatase inhibitors as compared to tamoxifen in adjuvant trials.[3-6] However, none of these trials screened for bone mineral density (BMD) before entry or included protocol-defined serial BMD screening or defined therapeutic intervention directed at BMD maintenance. Nonetheless, in the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial, potentially life-threatening hip fractures were rare (68 fractures in 6,142 participants in the two single-agent arms) with comparable incidence of anastrozole (Arimdex) and tamoxifen on hip fracture risk (1.2% vs 1.0%, respectively; P = .50). In current clinical practice the use of baseline screening and preventive interventions following available guidelines[7,8] should result in substantially lower fracture rates compared to those in the clinical trials.
The role of age, even relative to BMD, as a modulating fracture risk is receiving increasing attention. In the National Osteoporosis Risk Assessment cohort of 170,083 women, hip fracture incidence was extremely low in women aged 50 to 59 with no differences seen after 3 years comparing those with normal T scores, those with osteoporosis (T of -1.0 to -2.0) and those with greater bone loss (T of < -2.0). Similarly, in the ATAC trial total fracture incidence was significantly lower in younger women (< 60 years) compared to older women. The ATAC bone health substudy calls attention to the magnitude of BMD percent change needed to move a women with a normal BMD to the osteoporotic stage. In that study, no women with normal BMD at baseline became osteoporotic during the 5 years' duration of anastrozole use. This is not surprising, as a BMD loss of about 15% to 20% is needed to change a T score from the normal to the osteoporotic range.
We have become used to dichotomizing endometrial cancer risk related to tamoxifen by age (women < 50 years having substantially lower risk compared to older women). It appears we can similarly dichotomize fracture risk related to aromatase inhibitor use by age (< 60 years vs greater), with younger women at substantially less risk for hip fracture, especially. Consideration of bone turnover markers, as discussed by Perez and Weilbaecher, may further improve our ability to identify individual women at increased fracture risk.
Clinical oncologists may not be aware of the relatively modest absolute risk for hip fracture associated with bone loss, even in the osteoporotic range. In the Fracture Intervention Trial, 4,432 postmenopausal women with low bone mass and no prior fracture were randomized to the antiabsorptive agent alendronate (Fosamax) at 10 mg/d or placebo. After 4.2 years of follow-up, the hip fracture incidence in the 1,624 women with baseline T scores < -2.5 (osteoporotic range) was 2.2% for placebo vs 1.0% for alendronate (P = .04).
The potential contribution of low vitamin D status to bone health problems has recently been emphasized. In Norweigian early-stage breast cancer patients, 89% (108 of 121) had low (< 30 ng/mL) 25-hydroxyvitamin D levels at diagnosis. Similarly, in a large population of otherwise healthy US women entering a prevention trial, 85% (1,520 of 1,728) had low 25-hydroxyvitamin D levels. Thus, attention to vitamin D intake represents an integral component of bone health management.
There is theoretical concern that even temporary bone loss with associated disruption of bone architecture can result in long-term fracture risk increase. However, in the ATAC trial, total fracture incidence was comparable for women in the anastrozole and tamoxifen group when evaluated 6 months after the completion of the 5-year intervention trial. While further follow-up is needed, such results suggest long-term fracture risk may not continue after completion of aromatase inhibitor use.
Such considerations, and the emergence of potentially even more effective intervention strategies,[15,16] indicate that bone health problems related to aromatase inhibitor use can be successfully addressed.
-Rowan T. Chlebowski, MD, PhD
Financial Disclosure:Dr. Chlebowski is a consultant for AstraZeneca, Novartis, Pfizer, and Lilly, and receives grant support from Lilly and Amgen.
1. Chlebowski RT: Emerging trends in bisphosphonates therapy. Am J Oncol Review 5(3 suppl 1):20-26, 2006.
2. Goss PE, Chlebowski RT, LeBoff MS, et al: Recommendations on bone health management for women with early stage breast cancer. Am J Oncol Rev 5(3 suppl 1):34-43, 2006.
3. Howell A, Cuzick J, Baum M, et al: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365(9453):60-62, 2005.
4. Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793-1798, 2003.
5. Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two or three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081-1092, 2004.
6. Thurlimann B, Keshaviah A, Coates AS, et al: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353(26):2747-2757, 2005.
7. Hillner BE, Ingle JN, Chlebowski RT, et al: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21:4042-4057, 2003.
8. Winer EP, Hudis C, Burstein HJ, et al: ASCO technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: Status report 2004. J Clin Oncol 23:619-629, 2005.
9. Siris ES, Brenneman SK, Barrett-Connor E, et al: The effect of age and bone mineral on the absolute, excess, and relative risk of fracture in postmenopausal women aged 50-99: Results from the National Osteoporosis Risk Assessment (NORA). Osteoporos Int 17(4):565-574, 2006.
10. Howell A, on behalf of the ATAC Trialists' Group: Analysis of fracture risk factors from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial: 5 year data (abstract 563). J Clin Oncol 24(suppl 18S):18s, 2006.
11. Coleman RE, on behalf of the ATAC Trialists' Group: Effect of anatrozole on bone mineral density: 5-year result from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial (abstract 511). J Clin Oncol 24(supp 18S):5s, 2006.
12. Cummings SR, Black DM, Thompson DE, et al: Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 280(24):2077-2082, 1998.
13. Lonning P, Geisler J, Krag LE, et al: Vitamin D deficiency: A threat to bone health in breast cancer patients during adjuvant treatment with aromatase inhibitors. J Clin Oncol 24(suppl 18S):16s, 2006.
14. Chlebowski RT, Johnson KC, Kooperberg C, et al: The Women's Health Inititive randomized trial of calcium plus vitamin D: Effects on breast cancer, mammograms and arthralgias (LBA 6). J Clin Oncol 24 (suppl 18S):2s, 2006.
15. Lipton A, Alvarado C, DeBoer R, et al: Randomized, active-controlled study of denosumab (AMG 162) in breast cancer patients with bone metastases not previously treated with intravenous (IV) bisphosphonates (BP) (abstract 512). J Clin Oncol 24(suppl 18S):6s, 2006.
16. Chlebowski RT: Bone health in women with early stage breast cancer. Clin Breast Cancer 5(suppl 2):S35-S40, 2005.