The combined anti-osteoporotic effects of simvastatin and exercise in ovariectomized mice fed a high-fat diet

Background: To evaluate and compare the effects of the combined intervention of simvastatin and exercise on the bone degeneration in a mice model of osteoporosis (OP) induced by obesity and estrogen deficiency. Methods: 56 female 3-month-old C57BL/6 mice were given a standard diet or a high-fat diet after ovariectomy (OVX) or sham surgery. Drug administration and exercise training were initiated 72 h after surgical operation, which were treated with simvastatin (10 mg/kg/day) or exercise (15 m/min for 30 min/day) or combined with simvastatin and exercise at 72 h for 8 weeks. The pathology of OP was assessed by histomorphology analyses, immunohistochemistry (IHC), micro-computed tomography (Micro-CT), enzyme-linked immunosorbent assay (ELISA) and cell culture. Results: The coexistence of obesity and estrogen deficiency significantly further exacerbated OP pathology, and combined intervention showed a better significant anti-osteoporosis effect than monotherapy. In details, simvastatin combined with exercise ameliorated the abnormal bone mass, microstructure and bone marrow adipocyte differentiation, significantly increased osteoprotegerin (OPG), type 1 collagen (Col-I), RUNX2 and osteocalcin (OCN) expression, decreased the expression of receptor activator of nuclear factor-kappaB ligand (RANKL) and peroxisome proliferator-activated receptor gamma (PPAR gamma). Furthermore, combined intervention markedly improved abnormal metabolic status, reduced the levels of serum glucose, insulin, triglycerides (TG), low-density lipoprotein (LDL), leptin, CTX-1 and IL-1 beta, and increased the level of OCN. Conclusions: The coexistence of obesity and estrogen deficiency further aggravates bone tissue degeneration and abnormal metabolic pathology, which could be better inhibited by the combination with simvastatin and exercise instead of single intervention, suggesting that combined intervention may be a potential candidate for amelioration of the progression of OP.