In mice, drugs that lower testosterone (like GnRH agonists) hurt bone, but giving estrogen fixes the bone loss better than giving testosterone. Estrogen alone can also boost bone strength while keeping testosterone low, but it also ramps up bone‑cell activity that might help prostate cancer spread to bone.

Prostate cancer is a leading cause of death. As a hormone-driven cancer, prostate cancer is often treated with drugs (luteinizing hormone receptor agonists; LHRHa) or surgical approaches (orchidectomy; ORX) with the goal of reducing androgens. These approaches cause side effects such as bone loss. It is unclear if the side effects of these approaches are due to loss of androgens or loss of estrogens, as these approaches reduce both. We seek to evaluate if LHRHa and ORX have equivalent effects on bone, if the bone loss can be ameliorated by estrogen supplementation, and if estrogen supplementation alone is sufficient to improve bone mass while reducing androgen production. Herein, we evaluated bone microarchitecture, mechanical properties, and the cellular mechanism of LHRHa with subsequent hormone add-back on bone. We find that LHRHa negatively affects bone microarchitecture but has more mild effects on bone than ORX. Estrogen supplementation - but not androgen supplementation - improves bone mass and strength in mice treated with LHRHa. Estrogen supplementation alone is also sufficient to improve bone mass and strength while also reducing androgen production. However, estrogen supplementation also increases osteoblast and osteoclast activity, which may promote prostate cancer metastasis in bone. Future studies should evaluate estrogen as a modulator of the metastatic niche.