Combined Thermoneutral Housing and Raloxifene Treatment Improves Trabecular Bone Microarchitecture and Strength in Growing Female Mice

Abstract

Thermoneutral housing and Raloxifene (RAL) treatment both have potential for improving mechanical and architectural properties of bone. Housing mice within a 30 to 32 °C range improves bone quality by reducing the consequences of cold stress, such as shivering and metabolic energy consumption (Chevalier et al. in Cell Metab 32(4):575-590.e7, 2020; Martin et al. in Endocr Connect 8(11):1455-1467, 2019; Hankenson et al. in Comp Med 68(6):425-438, 2018). Previous work suggests that Raloxifene can enhance bone strength and geometry (Ettinger et al. in Jama 282(7):637-645, 1999; Powell et al. in Bone Rep 12:100246, 2020). An earlier study in our lab utilized long bones to examine the effect of thermoneutral housing and Raloxifene treatment in mice, but no significant interactive effects were found. The lack of an impact is hypothesized to be connected to the short 6-week duration of the study and the type of bone analyzed. This study will examine the same question within the axial skeleton, which has a higher proportion of trabecular bone. After 6 weeks of treatment with RAL, vertebrae from female C57BL/6 J mice underwent microcomputed tomography (μCT), architectural analysis, and compression testing. Most of the tested geometric properties (bone volume/tissue volume percent, trabecular thickness, trabecular number, trabecular spacing) improved with both the housing and RAL treatment. The effect sizes suggested an additive effect when treating mice housed under thermoneutral conditions. While ultimate force was enhanced with the treatment and housing, force normalized by bone volume fraction was not significantly different between groups. For longer pre-clinical trials, it may be important to consider the impacts of temperature on mice to improve the accuracy of these models.