Commentary (Lipton): Aromatase Inhibitors and Bone Loss

August 1, 2006

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.

In cancers associated with invasion of the skeleton, metastatic bone destruction leads to an increase in morbidity and a decrease in quality of life due to pain and fractures. However, bone complications are not only confined to patients with metastatic disease. Patients receiving anticancer treatments in the adjuvant setting are also at significant risk of fractures as a result of cancer treatment-induced bone loss. Cytotoxic chemotherapy can have a direct negative influence on bone mineral density (BMD), but other adjuvant treatments can also compromise bone integrity.

Aromatase inhibitors (AIs) have become widely used in early-stage breast cancer.[1-3] These agents significantly reduce circulating estrogen levels in postmenopausal women. Estrogen suppression results in a decrease in bone mineral density (BMD) in many women taking AIs. Similarly, adjuvant treatment for prostate cancer with GnRH agonists (eg, leuprolide and goserelin [Zoladex]) can induce premature andropause in men and also dramatically reduce BMD. The long-term use of both adjuvant treatments often increases the risk of fracture, with consequent deterioration in patient function and quality of life.[1-3,4]

Bisphosphonates in Cancer Treatment-Induced Bone Loss

The article by Perez and Weilbaecher is a very nice review of the causes of cancer treatment-induced bone loss and what can and should be done about it. Because of their high efficacy in preserving bone integrity and preventing bone complications, bisphosphonates are the standard of care for patients with metastatic bone disease. Bisphosphonates are also effective in preventing bone loss in the adjuvant setting. In chemotherapy-induced estrogen depletion, both clodronate (Bonefos)[5] and risedronate (Actonel)[6] significantly reduced bone loss compared with placebo, and pamidronate (Aredia) stabilized bone mineral density in androgen-deprived prostate cancer patients.[7] Ongoing studies with zoledronic acid (Zometa) include ABSCG-12, Z/ZO-FAST, and CALGB 79809 in breast cancer and others in prostate cancer.

Benefit of Up-Front Treatment

The still ongoing ABCSG-12 trial showed in a bone substudy that after 3 years of adjuvant treatment of premenopausal breast cancer patients, the groups not receiving zoledronic acid suffered a significantly higher loss of BMD than the groups receiving the bisphosphonate together with their standard therapy, irrespective of whether this was anastrazole (Arimidex) or tamoxifen plus goserelin.[8] Bone loss was most pronounced on the AI anastrozole, wheras the partial estrogen agonist tamoxifen depleted BMD to a lesser extent. ABCSG-12 clearly demonstrates that comedication can effectively prevent bone loss from adjuvant estrogen-depleting therapy.

These data are supported by the 12-month analysis from the Z-FAST trial.[9] Up-front comedication of zoledronic acid prevented bone loss. In contrast, 12% of the patients receiving delayed comedication of the bisphosphonate became osteopenic. In patients who were already osteopenic at baseline, up-front comedication of zoledronic acid effectively prevented further bone loss and even normalized BMD in about one-quarter of subjects, whereas delayed co-medication was only rarely able to normalize BMD, with a proportion of patients progressing to osteoporosis.

In prostate cancer patients, older bisphosphonates have been shown to reduce BMD loss with androgen-deprivation treatment. In an open-label study in 47 men, pamidronate prevented bone loss in the hip and lumbar spine during 1 year of prostate cancer treatment with leuprolide, a gonadotropin-releasing hormone agonist.[7] A similar trial with zoledronic acid not only reversed BMD loss but actually increased BMD over baseline in the hip and spine during androgen-deprivation therapy.[10] This is of particular interest to elderly patients who are already osteopenic at baseline.

Patients on Long-Term Hormone-Deprivation Therapy

According to current American Society of Clinical Oncology recommendations, all patients with breast or prostate cancer under hormone-deprivation treatment should have BMD determined at baseline and therafter at yearly intervals. Patients with a bone mineral density T score lower than -2.5 should receive adjuvant bisphosphates.[11,12] A treatment algorithm developed by the 3rd International Consultation on Prostate Cancer also recommends the use of a bisphosphonate for the prevention of skeletal complications in patients with bone metastases from prostate cancer, regardless of their hormone status, and for the prevention of treatment-induced bone loss in patients without evidence of bone metastases.[13]


Hormone-deprivation therapy has improved the results of adjuvant therapy in both breast and prostate cancer, but it can also lead to an unacceptable rate of reduction in BMD with ensuing risk of fractures and deterioration of the patients' functional independence.

Bisphosphonates are important agents for the prevention and treatment of cancer treatment induced bone loss. Many questions remain to be answered:Should a patient with a T score of -2.0 who has experienced bone loss be treated with a bisphosphonate? Should bisphosphonate treatment be started at the time of initiation of hormone deprivation therapy? Which bisphosphonate should be given: oral or IV? What is the long-term compliance with an oral bisphosphonate? How often should zoledronic acid be administered for cancer treatment-induced bone loss? Will fractures be prevented with the more potent bisphosphonates such as zoledronic acid and ibandronate? What about new bone drugs such as the antibody to RANKL (denosumab)?

More research is needed to optimize drug and treatment schedules for patient subgroups at particular risk.

-Allan Lipton, MD

Financial Disclosure:Dr. Lipton has served on speakers bureaus and acted as a consultant for Novartis and Amgen.


1. 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.

2. Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350(11)1081-1092, 2004.

3. Goss PE, Ingle JN, Martino S, et al: Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: Updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97(17):1262-1271, 2005.

4. Shahinian VB, Kuo YF, Freeman JL, et al: Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 352(2):154-164, 2005.

5. Saarto T, Blomqvist C, Valimaki M, et al: Clodronate improves bone mineral density in postmenpausal breast cancer patients treated with adjuvant antioestrogens. Br J Cancer 75(4):602-605, 1997.

6. Delmas P, Balena R, Confravreux E, et al: Bisphosphonate risedronate prevents bone loss in women with artificial menopause due to chemotherapy of breast cancer: A double blind, placebo-controlled study. J Clin Oncol 15(3):955-962, 1997.

7. Smith MR, McGovern FJ, Zietman AL, et al: Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 345(13):948-955, 2001.

8. Gnant M, Jakesz R, Mlineritsch B, et al: Zoledronic acid effectively counteracts cancer treatment induced bone loss (CTIBL) in premenopausal breast cancer patients receiving adjuvant endocrine treatment with goserelin plus anastrozole versus goserelin plus tamoxifen: Bone density subprotocol results of a randomized multicenter trial (ABCSG-12). San Antonio Breast Cancer Symposium, San Antonio, Texas, 2004.

9. Brufsky A, Harker WG, Beck JT, et al: Zoledronic acid (ZA) effectively inhibits cancer treatment-induced bone loss (CTIBL) in postmenopausal women (PMW) with early breast cancer (Bca) receiving adjuvant letrozole (Let): 12 mos BMD results of the Z-FAST trial. J Clin Oncol 23(16 suppl):533, 2005.

10. Smith MR, Eastham J, Gleason DM, et al: Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer. J Clin Oncol 22(14):2927-2941, 2004.

11. 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(21):4042-4057, 2003.

12. Loblaw DA, Mendelson DS, Talcott JA, et al: American Society of Clinical Oncology recommendations for the initial hormonal mamagement of androgen-sensitive metastatic, recurrent, or progressive prostate cancer. J Clin Oncol 22(14):2927-2941,2004.

13. Carroll PR, Altwein J, Brawley O, et al: Management of disseminated prostate cancer, in: Dennis L, Bartsch G, Khoury S, et al (eds): Prostate Cancer: 3rd International Consultation on Prostate Cancer, pp 249-284. Paris, Health Publications, 2003.