Effects of steroidal and nonsteroidal aromatase inhibitors (AIs) on markers of bone turnover and lipid metabolism in healthy volunteers

Abstract

8038 Background: Estrogen deprivation secondary to AI therapy raises concern about toxicities such as accelerated bone loss and consequent fracture risk in an elderly population, and alteration in lipid metabolism resulting in cardiovascular events. The steroidal AI exemestane (E) completely protects against ovariectomy (OVX)-induced bone loss in a menopausal rat model, while letrozole (L) does not. This may be related to weak androgenic activity of the principal metabolite of E, 17-hydroexemestane. Methods: Healthy postmenopausal volunteers were treated for 6 months with placebo (P), E, L or anastrozole (A). Assays at baseline and on wks 2, 4, 8, 12, 16, 20, 24, and 36 included: estradiol, estrone, estrone sulfate, serum (S) and urine (U) C-terminal telopeptide of type I collagen (S-CTx and U-CTx), S bone specific alkaline phosphatase (BAP), S procollagen type I aminoterminal propeptide (PINP), U N-terminal telopeptide of type I collagen (U-NTx) and lipids (total cholesterol, HDL, LDL, triglycerides [TG]). Primary bone endpoint was % change from baseline in biomarkers at 24 wks. Percent change in lipid profiles and estrogen concentrations were summarized by assessment time and treatment arm. Results: Data are available on 77 of 84 volunteers. Mean age: 58.2 yrs; mean BMI: 25 kg/m2. Avg time since menopause was 12.5 yrs; 100% Caucasian. Estrogens were suppressed below the level of detection by A, L, and E. Median % change of the bone resorption marker S-CTx at 12 wks was 12.82 (A), 22.05 (E), 17.17 (L), and 9.61(P). Median % change in the bone formation marker, P1NP from baseline at 12 wks was 2.43 (A), 16.89 (E), 0.38 (L), and 3.81 (P). The most striking finding in lipid assays was change in TGs: At 12 weeks, median TGs, as a % of baseline for each group were 78.7 (E), 107.4 (L), 98.3 (A), 101.8 (P). Conclusions: Bone resorption increased from all 3 AIs but E caused a presumptive androgenic increase in bone formation markers. TG levels were reduced by E in comparison to A and L. If this profile is confirmed, E could be the AI of choice in otherwise healthy postmenopausal women Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer, Inc. Pfizer, Inc. Pfizer, Inc.