Loss of estrogen results in reduced osteoblast mediated bone formation and enhanced osteoclastic resorption (Emmanuelle et al., 2021). Given the recent expansion of interest in understanding how these cellular processes are regulated via metabolic flux and bioenergetic capacity, there are several lines of indirect evidence that postmenopausal osteoporosis is a product of dysregulated intracellular metabolism in bone cells.  Glucose metabolism Osteoblast metabolism has been generally well characterized by our lab and others. This includes the finding that bone formation by the osteoblast is viewed as an energy demanding process whereby extracellular matrix proteins are synthesized and secreted along with mineralization vesicles (Borle et al., 1960a; Borle et al., 1960b). Metabolic substrates capable of generating adenosine triphosphate (ATP), osteoblasts can utilize glucose, glutamine, and fatty acids (Karner et al., 2015; Wei et al., 2015; Kim et al., 2017). The ability for osteoblasts to utilize glucose as a substrate is widely accepted in the bone biology field (Esen et al., 2013; Wei et al., 2015). Relative to these findings, Wei et al. (2015) published data describing GLUT1’s (Slc2a1) as the primary glucose transporter on osteoblasts, whereas data exists that both GLUT3 and GLUT4 are also expressed (Thomas et al., 1996; Zoch et al., 2016). To this end, mature osteoblasts generate ATP via glucose substrates using aerobic glycolysis (Jayapalan et al., 2022). In fact, cellular metabolic programming has been suggested to be the determining factor in deciding the lineage fate of the stromal cells in mice (Tencerova et al., 2019a). Adipo-progenitor cells have been shown to be more responsive to insulin and dependent on oxidative phosphorylation whereas the osteo-progenitor cells are more glycolytic. Interestingly, up-regulating glycolysis in adipo-progenitor cells by treating them with parathyroid hormone (PTH) decreases their adipogenic potential (Tencerova et al., 2019a). Even mesenchymal stromal cells from obese human have been shown to exhibit higher oxidative phosphorylation tendency and higher adipogenic potential (Tencerova et al., 2019b). While it has yet to be studied directly, it is plausible estrogen, or lack thereof in menopause, could regulate osteoblast glucose metabolism. For example, estrogen has been shown to activate GLUT4 in the intestine and GLUT1 in the brain (Gregorio et al., 2021). Estrogens have also been demonstrated to enhance glycolysis via intermediate metabolite regulation of phosphofructokinase (Alemany, 2021). Taken together, it is possible that similar pathways are also altered in osteoblasts given overlap in machinery. If this were the case, loss of estrogen as in menopause, would be expected to downregulate glucose transporters on osteoblasts and glycolysis, thereby reducing osteoblast activity. Microbiome/Ketones – Short chain fatty acids Estrogen modulates the intestinal microbiome in an interplay tailored to enhance the proliferation of beneficial bugs (Chen and Madak-Erdogan, 2016) Estrogen activates regulatory T-cells (Tregs), that prevents osteoclastogenesis and promote bone mass. Clostridia are well known producers of SCFAs, including butyrate. Butyrate maintains gut epithelial barrier, demonstrate immunomodulatory characteristics, and thus activates regulatory T cells (Furusawa et al., 2013). Another study done by Attarshi et al. reported that human Clostridia induce Tregs activity and contribute to systemic skeletal homeostasis (Atarashi et al., 2013). Lucas et al. performed a study comparing mice fed with short chain fatty acids (SCFAs) or high fiber diet and found a considerable increase in bone mass preventing postmenopausal and inflammatory bone loss (Lucas et al., 2018). Moreover, the SCFAs propionate (C3) and butyrate inhibit osteoclast differentiation and limits bone resorption in vitro and in vivo (Wallimann et al., 2021). Even more significantly, these two SCFAs incite osteoclast metabolism resulting in increased glycolysis at the expense of oxidative phosphorylation and thus downregulates osteoclast genes such as TRAF6 (TNF Receptor Associated Factor 6) and NFATc1 (Nuclear Factor of Activated T Cells 1) (Lucas et al., 2018). SOURCE