Irisin is a myokine produced by skeletal muscle during exercise in both mice and humans. We previously showed that irisin treatment ameliorates immobility‐induced osteoporosis and muscular atrophy in mice. Data in humans showed a positive association between irisin and bone mineral density (BMD) in athletes and a population of healthy children. However, the role of this myokine regarding the state of muscle and bone in the same population remained to be determined. For this purpose, 62 patients (age 68.71 ± 12.31 years) undergoing total hip or knee replacement were recruited. Our results showed that irisin serum levels negatively correlated with age (R = −0.515;​ p = .000018) and positively correlated with femoral BMD (R = 0.619;​ p = .001) and vertebral BMD (R = 0.201;​ p = .0001). Irisin was also positively associated with Fndc5 mRNA in muscle biopsies (R = 0.248;​ p = .016), as well as with Osteocalcin (Ocn) mRNA in bone biopsies (R = 0.708;​ p = .006). In skeletal muscle, FNDC5 positive fibers positively correlate with BMD of total femur (R = 0.765;​ p = .0014) and BMD of femoral neck (R = 0.575;​ p = .031), Interestingly, by analyzing patients divided by their T‐score, we found lower irisin levels (p = .0011) in patients with osteopenia/osteoporosis (OP) compared to healthy controls matched for age and sex. By analyzing the senescence marker p21, we found a significant increase of its mRNA expression in the bone biopsies of OP patients compared to control ones. Therefore, we investigated in vitro whether rec‐irisin had a direct effect on this senescence marker, showing that p21 mRNA expression was significantly downregulated in osteoblasts by the treatment with irisin. Overall, these results indicate that higher irisin levels are associated with a lower rate of age‐related osteoporosis and that irisin could be effective in delaying the osteoblast aging process, suggesting a potential senolytic action of this myokine.