Exemestane associated with significant bone loss in postmenopausal women

Cheung AM. Lancet Oncol. 2012;doi:10.1016/S1470-2045(11)70389-8.

Exemestane, a preventive breast cancer drug, was associated with significant bone loss in postmenopausal women despite calcium and vitamin D supplementation, according to research published in The Lancet Oncology.

Due to potential widespread use, researchers examined the safety of exemestane on bone health, focusing primarily on bone mineral density and structure. Analysis for this 2-year safety substudy was included as part of the Mammary Prevention 3 (MAP.3) trial, an outcome-driven, placebo-controlled, double-blind, randomized trial regarding the use of oral exemestane for the prevention of invasive breast in at-risk postmenopausal women.

“Exemestane worsens age-related decreases in bone mineral density by about three times, even in the setting of adequate calcium and vitamin D intake,” researcher Angela M. Cheung, MD, FRCPC, PhD, of the University Health Network, Toronto, said in a press release.

The safety substudy involved participants selected from three centers in Canada (Mount Sinai Hospital, Toronto General Hospital and Women’s College Hospital) and two in the United States (Mayo Clinic Rochester, University of California Davis Medical Center). In this substudy, researchers included women without osteoporosis, with a T-score of more than –2 at the lumbar spine, total hip and femoral neck. The score cutoff was selected to avoid the risk of pharmacological therapies masking the effects of exemestane on bone.

Exclusion factors for this substudy included:

Fragility fractures after the age of 40 years.
Drugs for treatment of bone-related disorders in the past 3 months.
Bisphosphonates for 6 months or more or strontium for 1 month or more.
Chronic oral steroids (>5 mg prednisone for >2 weeks in the past 6 months).
Malabsorption.
Metabolic bone disease.
Inflammatory diseases.

Three hundred fifty-one postmenopausal women met inclusion criteria and completed baseline assessment. They were randomly assigned to receive either exemestane (n=176) or placebo (n=175). At the time of clinical cutoff, 242 women had completed the 2-year follow-up (exemestane=124; placebo=118).

According to X-ray absorptiometry and peripheral quantitative CT assessments, from baseline to 2 years, the mean percent change in total volumetric bone mineral density at the distal radius was –6.1% (95% CI, –7 to –5.2) in the exemestane group and –1.8% (95% CI, –2.4 to –1.2) in the placebo group (difference of –4.3%, 95% CI, –5.3 to –3.2).

Assessments of the distal tibia revealed the mean percent change in total volumetric bone mineral density was –5% (95% CI, –5.5 to –4.4) in the exemestane group and –1.3% (95% CI, –1.7 to –1) in the placebo group (difference of –3.7%, 95% CI, –4.3 to –3).

In addition, by the 2-year follow-up, mean cortical thickness at the distal radius changed by –7.9% in the exemestane group and –1.1% in the placebo group (difference of –6.8%; 95% CI, –8.5 to –5), and mean cortical thickness at the distal tibia changed by –7.6% in the exemestane group and –0.7% in the placebo group (difference of –6.9%; 95% CI, –8.4 to –5.5). Researchers observed that mean total area and mean cortical area also declined with exemestane compared with placebo at both sites.

“Our study showed that 2 years of exemestane had a negative effect on bone density and structure in postmenopausal women,” the researchers wrote. “Because this study is only comparing exemestane with placebo, we do not know how it compares with other aromatase inhibitors in terms of their effects on bone density and structure. Although we cannot extrapolate these intermediate endpoints to changes in fracture risk, the findings of our study suggest that we need to weigh the individual risks and benefits when considering exemestane for the primary prevention of breast cancer.”

Disclosure: The researchers reported receiving consulting support from Pfizer.

Earn CME this spring at the HemOnc Today Breast Cancer Review & Perspective meeting to be held March 23-24, 2012 at the Hilton San Diego Bayfront. See details at HemOncTodayBreastCancer.com.

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