The mechanical characteristics of the extracellular matrix (ECM) are essential for cellular behaviors, particularly for mesenchymal stem cells (MSCs) that regulate osteogenic differentiation during bone formation. While mechanical cues and metabolic reprogramming have been studied separately, there is insufficient understanding of their interrelationship, representing an important gap in our overall knowledge about stem cell fate and bone tissue engineering. This review highlights recent research regarding the regulation of glucose metabolism by ECM stiffness during osteogenic differentiation, integrating data from mechanotransduction with metabolic pathways. It presents findings from both in vitro and in vivo studies that start to define additional important mechano-sensitive pathways that convert ECM stiffness into greater glycolysis and enhanced mitochondrial function providing the energy and biosynthetic resources needed for differentiation. In this review, we consolidate ongoing fragmented research into new frameworks that integrate pathways more comprehensively and demonstrate its importance to generating stiffness optimized biomaterials that have regenerative potential.