How Exercise Reprograms Glucose Metabolism to Fight Osteoporosis

Osteoporosis, the skeletal disease in which bone mass declines and microarchitecture deteriorates until fractures become likely, affects roughly 23 percent of women and 12 percent of men worldwide according to large meta-analyses, and its burden is growing as populations age. For decades, clinicians have recommended exercise as a safe, non-pharmacological way to slow bone loss, but the molecular machinery linking a treadmill session to stronger bone has remained frustratingly opaque. A new narrative review published in Sports Medicine – Open now argues that a surprising suspect sits at the center of that machinery: glucose metabolic reprogramming, the process by which cells switch their fuel-burning strategies to meet changing demands. Drawing on 144 studies screened from an initial pool of 735, the authors, led by Chu Li and Yu Yuan of Guangzhou Sport University, assemble evidence that the fate of nearly every cell in bone hinges on how it burns sugar, and that exercise reshapes those metabolic choices in ways that protect the skeleton.

The review’s central premise is that bone is not the metabolically inert scaffold it might appear to be. Its resident cells constantly make lineage decisions that determine whether the skeleton is built up or torn down, and those decisions are powered by two competing energy pathways: glycolysis, the rapid but inefficient cytoplasmic conversion of glucose to lactate, and oxidative phosphorylation, the slower but far more efficient mitochondrial route that feeds pyruvate into the tricarboxylic acid cycle. Only about 30 to 40 percent of the energy released during glucose processing is captured as adenosine triphosphate, the cell’s energy currency, so how a cell partitions flux between these pathways matters enormously. The authors contend that shifts among glycolysis, the pentose phosphate pathway, and the TCA cycle act as critical regulators of bone homeostasis, the delicate equilibrium between bone-forming osteoblasts and bone-resorbing osteoclasts.

The story begins with bone marrow mesenchymal stem cells, the multipotent progenitors that can become either osteoblasts or fat cells. When these stem cells commit to the bone-forming lineage, their metabolism undergoes a dramatic remodel, and here the review highlights a striking species divide. In most human and rat studies, stem cells undergoing osteogenic differentiation shift their metabolic flux toward oxidative phosphorylation, with glycolytic activity falling as mitochondria take over. Mouse cells behave in the opposite manner: glycolysis is progressively enhanced during the middle and late stages of osteogenesis, eventually displacing oxidative phosphorylation as the dominant energy source. The authors stress that glycolysis and oxidative phosphorylation cooperate rather than compete, but they also flag this species discrepancy as a critical translational gap, since most mechanistic data derive from murine models while human data remain scarce.

Several molecular players emerge as master switches in this system. Mitochondrial activity elevates production of acetyl-CoA, which supplies the acetyl groups needed to acetylate β-catenin, a modification that may promote its entry into the nucleus and activation of the Wnt/β-catenin pathway, a canonical driver of bone formation. The microRNA miR-34a suppresses the glycolytic enzyme lactate dehydrogenase A, thereby dampening glycolysis and inhibiting osteogenic differentiation, while stabilizing hypoxia-inducible factor 1α upregulates glucose transporter 1 and pyruvate dehydrogenase kinase 1, boosting aerobic glycolytic flux and pushing stem cells toward the bone lineage. In aged mice, the authors note, both glycolytic capacity and oxidative phosphorylation decline in mesenchymal stem cells, a metabolic impairment that plausibly contributes to the reduced bone formation and increased marrow fat characteristic of osteoporotic bone, although whether this mechanism directly drives human disease remains unproven.

Osteoblasts, the terminally differentiated matrix-depositing cells, tell a complementary metabolic tale. Early studies established glucose as their predominant endogenous fuel, and during differentiation these cells rely heavily on glycolysis, particularly in the final mineralization stage. Glucose enters through facilitative transporters of the GLUT family, with GLUT1 mediating most uptake; deleting GLUT1 in osteoblast precursors impairs differentiation, while inactivating GLUT4 suppresses pre-osteoblast proliferation. The mechanistic target of rapamycin pathway adds another layer of control: mTORC1 acts as a metabolic brake that limits osteoblast glucose utilization, whereas mTORC2, activated downstream of the WNT-LRP5 signaling cascade via the kinase AKT, drives expression of glycolytic enzymes and enhances differentiation. Insulin and the energy sensor AMPK further modulate the picture, with AMPK activation promoting mineralization through autophagy in some studies yet upregulating the bone-formation inhibitor sclerostin in others, a reminder that metabolic regulation in bone is rarely one-directional.

Osteoclasts, the bone-resorbing counterparts, also depend intimately on glucose metabolism. When their precursors receive the RANKL signal, mitochondrial mass and oxidative phosphorylation expand to power osteoclastogenesis, but as the cells mature, glycolysis takes center stage: glucose consumption and lactate production rise, GLUT1 and glycolytic enzymes such as hexokinase 2 and pyruvate kinase M2 are upregulated, and hypoxia-inducible factor 1α, triggered by the low-oxygen environment of resorption cavities, sustains this glycolytic program. Lactate, the glycolytic end product, does double duty, maintaining redox balance, driving histone lactylation, and acidifying the local microenvironment to facilitate resorption. Transporters MCT1 and MCT2 export lactate, and blocking them with the inhibitor AZD3965 accumulates intracellular lactate, suppresses glycolytic enzymes, and inhibits osteoclast differentiation without harming osteoblasts in preclinical models, hinting at a metabolically targeted anti-resorptive therapy.

Against this backdrop, the review’s most provocative section addresses how exercise intervenes. One pathway runs through muscle-derived extracellular vesicles, tiny membrane-bound packages that contracting skeletal muscle releases into the circulation. When these vesicles are taken up by bone marrow stem cells, they deliver the glycolytic enzyme lactate dehydrogenase A, increasing glucose consumption, lactate production, and osteogenic differentiation; in mouse models of disuse osteoporosis, supplementing these vesicles restored glycolytic activity in bone tissue. Exercise intensity appears decisive, with high-intensity efforts inducing substantially greater vesicle release than moderate activity. Mechanical stress also acts directly: cyclic stretching of osteoblast-like cells increased glucose consumption, lactate, and ATP while activating the Akt/mTOR/p70S6K pathway, and fluid shear stress and vibration training promoted both glycolysis and the TCA cycle in bone cells.

Hormonal and systemic routes complete the picture. Exercise stimulates secretion of parathyroid hormone, which reshapes osteoblast metabolism by boosting glucose uptake and lactate production through IGF signaling while blocking glucose entry into the TCA cycle, a metabolic shift that underlies the hormone’s bone-building effects. Aerobic exercise upregulates PGC-1α, which in inflammatory environments shifts bone remodeling toward glycolysis-dependent bone formation and away from resorption. Resistance training raises irisin, a myokine that promotes osteoblast proliferation by enhancing glycolysis. Perhaps most strikingly, high-intensity interval training upregulates the glycolytic regulator PKM2 in endothelial cells, and the lactate they release triggers histone lactylation in bone marrow stem cells, directly activating osteogenic genes such as collagen type I alpha 2; osteoporosis patients show lower serum lactate than healthy controls, and lactate supplementation restored bone density in ovariectomized mice.

The authors are careful to temper enthusiasm with caveats. Nearly all mechanistic evidence comes from rodents or in vitro systems, no study has directly measured glucose metabolic flux in bone cells from exercising humans, and the exercise protocols used in animal models may not translate safely to frail patients at high fracture risk. Human imaging work does offer support: a study using fluorodeoxyglucose PET/CT showed that wearing a weighted vest elevated glucose uptake in the loaded limb’s muscles, cortical bone, and bone marrow, confirming that mechanical loading raises local energy demand in the musculoskeletal complex. Still, the duration, intensity, and frequency of exercise needed to achieve metabolic bone benefits in people remain unknown.

Nevertheless, the review sketches a practical horizon. The authors suggest that high-intensity interval training to boost endothelial lactate, resistance training to raise irisin, and mechanical loading to activate the PGC-1α/LDHA axis may each optimize glucose metabolism in bone, while recommending a prudent clinical default of weight-bearing aerobic exercise three to five times weekly combined with resistance training two to three times weekly, avoiding high-impact activities in established osteoporosis. Future priorities include stable isotope tracer studies to map glucose flux across species, human exercise trials tracking circulating lactate alongside bone formation markers, and cross-species metabolomics to separate universal principles from species quirks. If those efforts succeed, the humble sugar molecule may prove to be the missing link between a morning run and a fracture-free old age.

Subject of Research: The role of glucose metabolic reprogramming in how exercise attenuates osteoporosis

Article Title: The Role of Glucose Metabolic Reprogramming in Exercise-Attenuated Osteoporosis: a Narrative Review

Article References: Li, C., He, Y., Weng, K., Zhang, S., Weng, X., & Yuan, Y. (2026). The Role of Glucose Metabolic Reprogramming in Exercise-Attenuated Osteoporosis: a Narrative Review. Sports Medicine – Open, 12(1), Article 152. https://doi.org/10.1186/s40798-026-01121-x

Image Credits: AI Generated

DOI: 10.1186/s40798-026-01121-x

Keywords: osteoporosis, exercise, glucose metabolism, glycolysis, oxidative phosphorylation, bone remodeling, osteoblasts, osteoclasts, mesenchymal stem cells, lactate, parathyroid hormone, metabolic reprogramming