Cortical and trabecular deterioration in mouse models of Roux-en-Y gastric bypass

Abstract

Roux-en-Y gastric bypass (RYGB) is a profoundly effective treatment for severe obesity, but results in significant bone loss in patients. Developing a murine model that recapitulates this skeletal phenotype will provide a robust tool with which to study the physiologic mechanisms of this bone loss. We studied adult male C57BL/6J mice who underwent either RYGB or sham operation. Twelve weeks after surgery, we characterized biochemical bone markers (parathyroid hormone, PTH; C-telopeptide, CTX; and type 1 procollagen, P1NP) and bone microarchitectural parameters as measured by microcomputed tomography. RYGB-treated mice had significant trabecular and cortical bone deficits compared with sham-operated controls. Although adjustment for final body weight eliminated observed cortical differences, the trabecular bone volume fraction remained significantly lower in RYGB mice even after weight adjustment. PTH levels were similar between groups, but RYGB mice had significantly higher indices of bone turnover than sham controls. These data demonstrate that murine models of RYGB recapitulate patterns of bone loss and turnover that have been observed in human clinical studies. Future studies that exploit this murine model will help delineate the alterations in bone metabolism and mechanisms of bone loss after RYGB.

Keywords: Bariatric surgery; Bone loss; Bone microarchitecture; Gastric bypass; Mouse models; Obesity; Weight loss.

Figure 1. Body weight changes in RYGB (solid line) and sham-operated (dashed line) mice

Between 23 to 26 weeks of age (average 25 weeks), mice were randomized to RYGB or sham surgery and followed for 12 weeks. RYGB mice lost approximately 30% of their initial weight and maintained the loss thereafter, while sham-operated mice exhibited transient weight loss, with subsequent regain to a body weight approximately 20% greater than their initial weight.

Fig. 2. Representative images of bone microarchitecture in RYGB (right) and sham-operated (left) mice

Defects in trabecular microarchitecture are apparent after RYGB at the L5 vertebrae (A). Abnormal bone geometry and microarchitecture are shown after RYGB at the proximal tibia metaphysis (B) and mid-shaft tibia (C).

Fig. 3. Indices of bone turnover and PTH levels in RYGB and sham-operated mice

Boxplots showing median, interquartile range, maximum and minimum values are displayed. Twelve weeks after surgery, CTX (A) and P1NP (B) levels were significantly greater in the RYGB mice than in sham controls. There was no difference in PTH between RYGB and sham groups (C). ** p ≤ 0.005.