Peak trabecular bone microstructure predicts rate of estrogen-deficiency-induced bone loss in rats

Abstract

Postmenopausal osteoporosis affects a large number of women worldwide. Reduced estrogen levels during menopause lead to accelerated bone remodeling, resulting in low bone mass and increased fracture risk. Both peak bone mass and the rate of bone loss are important predictors of postmenopausal osteoporosis risk. However, whether peak bone mass and/or bone microstructure directly influence the rate of bone loss following menopause remains unclear. Our study aimed to establish the relationship between peak bone mass/microstructure and the rate of bone loss in response to estrogen deficiency following ovariectomy (OVX) surgery in rats of homogeneous background by tracking the skeletal changes using in vivo micro-computed tomography (μCT) and three-dimensional (3D) image registrations. Linear regression analyses demonstrated that the peak bone microstructure, but not peak bone mass, was highly predictive of the rate of OVX-induced bone loss. In particular, the baseline trabecular thickness was found to have the highest correlation with the degree of OVX-induced bone loss and trabecular stiffness reduction. Given the same bone mass, the rats with thicker baseline trabeculae had a lower rate of trabecular microstructure and stiffness deterioration after OVX. Moreover, further evaluation to track the changes within each individual trabecula via our novel individual trabecular dynamics (ITD) analysis suggested that a trabecular network with thicker trabeculae is less likely to disconnect or perforate in response to estrogen deficiency, resulting a lower degree of bone loss. Taken together, these findings indicate that the rate of estrogen-deficiency-induced bone loss could be predicted by peak bone microstructure, most notably the trabecular thickness. Given the same bone mass, a trabecular bone phenotype with thin trabeculae may be a risk factor toward accelerated postmenopausal bone loss.

Keywords: Bone loss predictor; Bone mechanical properties; Bone microstructure; In vivo micro-computed tomography; Osteoporosis; Ovariectomy.

Figure 1.

(A) Representative 3D renderings of the proximal tibia pre- (wk0) and post-OVX (wk4); (B-G) Trabecular structural parameters, including (B) BV/TV, (C) Tb.N, (D) Tb.Th, (E) Tb.Sp, (F) SMI, and (G) Conn.D at 0 and 4 weeks post-OVX. (H) FEA-derived Tb.Stiffness at 0 and 4 weeks post-OVX. * indicates significant changes over time (p<0.05).

Figure 2.

(A-C) Representative trabecular bone images in Low, Medium, and High relative Tb.Th groups. Heat maps correspond to local trabecular thickness values. (D) Rats were stratified into Low, Medium, and High relative Tb.Th by performing linear regression of baseline Tb.Th and BV/TV. (E) Baseline BV/TV was not different between Low, Medium, and High relative Tb.Th groups. (F) Comparisons of baseline Tb.Th among Low, Medium, and High relative Tb.Th groups. (G-L) % changes in trabecular bone parameters, including (G) BV/TV, (H) Conn.D, (I) Tb.N, (J) Tb.Sp, and (K) Tb.Th, in Low, Medium, and High relative Tb.Th groups over 4 weeks post-OVX. (L) % decrease in FEA-derived Tb.Stiffness in Low, Medium, and High relative Tb.Th groups. * indicates significant differences between groups (p<0.05).

Figure 3.

(A) Schematics of individual trabecular dynamics analysis. (B) % bone loss in individual trabeculae stratified by baseline thickness. (C) Probability density distribution of the baseline thickness of deteriorated and intact trabeculae. (D-E) Schematics of accelerated bone resorption followed by osteoblast repair in (D) a thick and (E) a thin trabecula. * indicates significant differences between groups (p<0.05).