Metabolic aging of the skeleton: mechanisms and therapeutic opportunities in osteoporosis

Beyond the classical imbalance between bone formation and resorption, osteoporosis is increasingly linked to age-related disruption of skeletal cell metabolism. Osteoblasts, osteoclasts, osteocytes, and bone marrow stromal cells rely on distinct combinations of glycolysis, oxidative phosphorylation, fatty acid metabolism, and glutamine utilization to support matrix production, mineralization, and bone resorption. These metabolic programs are progressively disturbed with aging by mitochondrial dysfunction, oxidative stress, depletion of nicotinamide adenine dinucleotide (NAD + ), altered nutrient-sensing pathways, bone marrow adiposity, and cellular senescence. This review summarizes the potential effects of these changes on bone remodeling and reframes currently approved anti-osteoporotic agents from a metabolic perspective. For bisphosphonates, denosumab, calcitonin, selective estrogen receptor modulators, teriparatide, and romosozumab, a distinction is made between the relatively few instances in which metabolic effects have been measured directly in skeletal cells and the larger number of effects inferred from the pathways targeted by these agents. Emerging approaches that more directly target skeletal metabolism are also discussed, including NAD + repletion, CD38 inhibition, mitochondria-targeted antioxidants, modulation of adenosine monophosphate-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR), senolytics, senomorphics, and metabolic-substrate-based or nutritional interventions. Although these strategies may provide opportunities to target processes upstream of the final bone remodeling imbalance, their translation is constrained by metabolic heterogeneity among cell types, systemic off-target effects, and narrow therapeutic windows for treatment timing and dose. Future therapeutic strategies may require metabolic subtyping, bone-selective delivery, and rational combinations with established anabolic or antiresorptive drugs to restore skeletal metabolic resilience during aging. Clinical trial number Not applicable.