Extracellular vesicles (EVs) have emerged as fundamental pillars of intercellular communication, acting as primary mediators of the bidirectional biochemical crosstalk within the integrated bone–muscle unit. This review provides a comprehensive synthesis of EV-mediated signaling across the bone–muscle axis, offering a side-by-side mapping of vesicular biogenesis, cargo composition, and functional roles in both tissues. Under physiological conditions, skeletal muscle- and bone-derived EVs orchestrate tissue homeostasis, adaptations to physical exercise, myogenesis, and bone remodeling by transferring unique molecular cargos of proteins and specific microRNAs. However, aging induces a profound remodeling of the EV secretome toward a senescent profile characterized by harmful vesicular factors. This dysfunctional vesicular signaling impairs both muscle regeneration and osteogenesis, directly contributing to the pathogenesis of interconnected age-related disorders like sarcopenia, osteoporosis, and osteosarcopenia. Concurrently, circulating EVs represent valuable, minimally invasive biomarkers for early diagnosis. On the therapeutic front, this review critically evaluates emerging EV-based approaches, utilizing mesenchymal stem cell-derived, bioengineered, or biomaterial-incorporated EVs, offering promising, low-immunogenic alternatives to cell transplantation to enhance musculoskeletal tissue repair and restore bone–muscle homeostasis. Despite persisting technical challenges regarding large-scale production and standardization, targeting or leveraging EV-mediated communication represents one of the most innovative and revolutionary strategies to counteract age-related musculoskeletal decline. By unifying physiological mechanisms, age-related molecular reprogramming, and therapeutic engineering across both muscle and bone into a single narrative, this review provides a comprehensive framework to guide future research and clinical translation in musculoskeletal health.

Background/Objectives: Osteoporosis and osteoarthritis are age-related musculoskeletal disorders with a high socio-health burden, affecting both healthcare systems and individuals’ quality of life. Both conditions are generally accompanied by a concomitant decline in muscle mass and strength, referred to as sarcopenia. In this context, tensiomyography emerges as a novel, non-invasive potential diagnostic strategy for assessing muscle quality, as this parameter influences the progression of both conditions. Methods: Histomorphometric and immunohistochemical analyses were performed on vastus lateralis muscle tissue obtained from patients undergoing surgery for femoral fracture affected by osteoporosis or osteopenia, patients operated for hip osteoarthritis, and patients undergoing hip arthroplasty for osteoarthritis, concomitantly affected by osteoporosis or osteopenia. In addition, muscle function was assessed in these patients using tensiomyographic analysis. Results: In osteoarthritic, osteoporotic, and osteopenic patients, a reduction in muscle quality and function was observed compared with the other two experimental groups, indicating an unfavorable effect of the coexistence of the two conditions on the muscular component. Furthermore, contraction time (Tc) measured by tensiomyography was negatively correlated with lumbar spine bone mineral density values and positively correlated with the percentage of type II muscle fibers. Conclusions: This study highlights how tensiomyography may represent a valuable non-invasive diagnostic strategy for assessing muscle status in osteoporotic and osteoarthritic patients, as it is able to detect muscle alterations that parallel the worsening of bone status and that cannot be inferred from simple biopsy analysis. Thus, tensiomyography could be considered a practical adjunct tool in the clinical assessment of musculoskeletal frailty.