Both compounds bind the estrogen receptor, but the resulting receptor conformation differs in ways that alter coactivator/corepressor recruitment by tissue. Raloxifene's conformation favors antagonist activity in both breast and endometrial tissue, whereas tamoxifen retains partial agonist activity in the endometrium.

This divergence makes head-to-head SERM studies a common approach for mapping how structural differences in ligands translate into tissue-specific transcriptional outcomes.

Because raloxifene's receptor conformation in bone tissue favors estrogen-agonist-like signaling, it is used in osteoblast/osteoclast culture models and in vivo bone density studies to examine estrogen-receptor-mediated effects on bone turnover, independent of the antagonist activity it shows in reproductive tissue.

Raloxifene undergoes extensive glucuronidation rather than requiring CYP2D6-mediated bioactivation, unlike tamoxifen, which depends on CYP2D6 conversion to its active metabolite endoxifen. This makes raloxifene a useful comparator in research examining how metabolic activation requirements affect SERM activity and inter-individual variability tied to CYP2D6 polymorphisms.