Effects of (R)-ketamine on reduced bone mineral density in ovariectomized mice: A role of gut microbiota

Depression is a high risk for osteoporosis, suggesting an association between depression and low bone mineral density (BMD). We reported that the novel antidepressant (R)-ketamine could ameliorate the reduced BMD in the ovariectomized (OVX) mice which is an animal model of postmenopausal osteoporosis. Given the role of gut microbiota in depression and bone homeostasis, we examined whether gut microbiota plays a role in the beneficial effects of (R)-ketamine in the reduced BMD of OVX mice. OVX or sham was operated for female mice. Subsequently, saline (10 ml/kg/day, twice weekly) or (R)-ketamine (10 mg/kg/day, twice weekly) was administered intraperitoneally into OVX or sham mice for the six weeks. The reduction of cortical BMD and total BMD in the OVX mice was significantly ameliorated after subsequent repeated intermittent administration of (R)ketamine. Furthermore, there were significant changes in the alpha- and beta-diversity between OVX + saline group and OVX + (R)-ketamine group. There were correlations between several OTUs and cortical (or total) BMD. There were also positive correlations between the genera Turicibacter and cortical (or total) BMD. Moreover, there were correlations between several metabolites in blood and cortical (or total) BMD. These data suggest that (R)-ketamine may ameliorate the reduced cortical BMD and total BMD in OVX mice through anti-inflammatory actions via gut microbiota. Therefore, it is likely that (R)-ketamine would be a therapeutic drug for depressed patients with low BMD or patients with osteoporosis.