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.
Role of Age in Fracture Risk
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).
Vitamin D Intake
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.
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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.