Background

Tamoxifen (TAM) is used to treat estrogen receptor positive breast cancer. While adjuvant and preventive TAM is primarily prescribed to premenopausal women, preclinical studies evaluating bone structure and strength in response to TAM have largely been limited to the estrogen-deficient state (i.e., OVX). Further, obesity increases the risk of breast cancer and worsens metabolic outcomes after TAM treatment; yet, the effects of TAM on fracture risk in the obese state are unknown. We hypothesized that obesity modified bone geometry and strength in estrogen replete mice in response to TAM treatment.

Methods

Juvenile female mice were given high-fat (HFD) or low-fat diets (LFD) and housed at thermoneutrality to induce obesity. Mature mice underwent ovariectomy (OVX) and were given estrogen (E2) add back with or without Tamoxifen for 2 weeks.

Results

TAM did not significantly alter cortical bone in LFD mice. In contrast, trabeculae were thicker in HFD and TAM, and bone volume fraction was higher in HFD; yet, trabecular number and specific bone surface (BS/BV) were decreased in HFD and in TAM. TAM decreased connectivity density, and the structural model index (SMI) suggested a rod-like, rather than plate-like, network with TAM. In HFD mice, TAM decreased the cortical area fraction (-8.1%; 38.3±0.8 vs 35.2±2.6%), modulus (-9.2%) and resistance to bending (-13.8%; 0.052±0.002 vs 0.050±0.005 mm4; Mean±SD) about the minor bone axis. This was a result of decreasing cortical thickness.

Conclusions

In the presence of E2, short-term TAM exerts negative effects on cancellous bone, regardless of adiposity. Cortical bone loss was demonstrated in HFD, but not LFD. TAM may reduce bone strength in women with a high BMI, which indicates a higher fracture risk and warrants specific follow-up for these breast cancer patients.