According to the results of a subanalysis of the MAP.3 study, exemestane used for the prevention of breast cancer in healthy postmenopausal women appears to worsen age-related decreases in total volumetric BMD at the distal radius and distal tibia, even in the setting of adequate calcium and vitamin D intake.

The authors note that aromatase inhibitors have the potential to adversely affect bone health because they can substantially reduce circulating oestrogen levels and thereby increase bone resorption.  The majority of previous studies evaluating the effects of these medicines on bone were conducted in women with breast cancer and used tamoxifen as a comparator, which has been shown to increase BMD and decrease fractures in postmenopausal women.  It is therefore unclear how these results translate to a healthy postmenopausal population, taking such medicines for the primary prevention of breast cancer.  

The MAP.3 study investigated exemestane 25mg a day for the primary prevention of breast cancer, and was published in the New England Journal of Medicine in 2011 (please see link below for an NeLM summary of the study, including its design and main findings).  The current publication describes the results of a nested substudy of this trial, which examined the safety of exemestane on bone health; focusing on the intermediate endpoints of bone density and structure (the assessment of fracture outcomes was not possible as the study was underpowered for this).      

The substudy included women who were not osteoporotic, not receiving drugs for bone-related disorders, with baseline lumbar spine, total hip and femoral neck T-scores above −2.0 at baseline (n=351; 176 randomised to exemestane and 175 to placebo).  The primary endpoint was percent change from baseline to 2 years in total volumetric bone mineral density (BMD) at the distal radius.  At the time of clinical cut-off, 242 women had completed 2-year follow-up (124 given exemestane, 118 given placebo). The main findings reported were as follows (per-protocol analysis):

• The mean percentage change in total volumetric BMD at the distal radius at 2 years (primary endpoint) was −6.1% (95% CI -7.0 to -5.2) in the exemestane group and −1.8% (-2.4 to -1.2) in the placebo group.

• The difference between the groups was -4.3% (95% CI -5.3 to -3.2; p<0.0001); the lower limit of the 95% CI was below the pre-defined non-inferiority margin of -4% and therefore the hypothesis that exemestane was inferior could not be rejected.

• The mean percentage change in total volumetric BMD at the distal tibia at 2 years was -5.0% (95% CI -5.5 to -4.4) in the exemestane group and -1.3% (-1.7 to -1.0) in the placebo group (difference of -3.7%, 95% CI -4.3 to -3.0; p<0.0001).

• The exemestane group also showed negative effects on a number of other secondary endpoints, including cortical thickness and areal BMD.

The authors comment that the changes seen implicate the loss of cortical bone, likely secondary to the loss of oestrogen.  As the study is comparing exemestane with placebo, it is not known how it compares with other aromatase inhibitors, and the results for BMD cannot be extrapolated to changes in fracture risk.  They conclude however that the individual risks and benefits of receiving exemestane in the primary prevention setting need to be weighed up, and that regular bone monitoring and adequate calcium and vitamin D supplementation are important for those that do receive this treatment.