In Reply to the Letter to the Editor: Involvement of Irisin in Age‐Related Osteoporosis and Its Inhibitory Effect on the Senescent Marker p21 in Osteoblasts

We appreciate the thoughtful letter from Professor Naharci regarding our recently published article showing that irisin correlates positively with bone mineral density (BMD) in a cohort of older adult patients and downregulates the senescent marker p21 in osteoblasts. We thank him for the interest in our recent work and welcome the opportunity to respond to his comments. As noted by Naharci, several chronic diseases could have influenced the levels of circulating irisin measured in our cohort of older adult patients. In agreement with this premise, in our study, we enrolled patients by excluding all subjects with at least one chronic disease. Because our primary outcome was to investigate possible links between circulating irisin, FNDC5 expression in skeletal muscle, and BMD, the main exclusion criteria were taking anti-osteoporosis therapy and physical impairments affecting the performance of daily activities. However, subjects were also excluded if they had renal failure with glomerular filtration rate <30 mL/min, diastolic blood pressure >90 mmHg, systolic blood pressure >140 mmHg, any impairment of glucose metabolism such as diabetes or pre-diabetes, glucocorticoid use within the past 2 years, and thyroid, parathyroid, and liver diseases. Future studies aimed at performing similar investigations on irisin in osteoporosis and muscle atrophy will certainly be relevant, including comparisons between possible comorbidities. However, we considered that this type of investigation was premature in our study because there is not yet univocal consensus about the alteration of circulating irisin in chronic diseases, such as diabetes and hypertension. Regarding diabetes, a human study reported that circulating irisin levels were significantly higher in diabetic patients than in healthy subjects. However, meta-analysis showed that irisin levels were lower in type 2 diabetic patients than nondiabetic patients. Additionally, a cross-sectional observational study including 102 patients with type 2 diabetes showed that irisin, although not significantly, tended to be higher in patients with abnormal fasting glucose compared with those with normal fasting glucose. Therefore, despite the promising role of irisin for the treatment of diabetes, its involvement in glucose metabolism needs to be further investigated. As noted by Naharci, some studies have provided evidence that irisin is associated with the regulation of blood pressure. Studies in animal models indicated that irisin lowers blood pressure and thus contributes to the antihypertensive effect. However, clinical studies have not been conclusive in demonstrating association between irisin and blood pressure. One of the first studies published after the discovery of irisin found no significant difference in irisin levels between untreated hypertensive patients and controls. In ameta-analysis from 741 studies, the pooled data indicated that irisin levels were lower in patients with cardiovascular disease or atherosclerosis than in healthy controls. Low irisin levels were also found to be a prognostic marker of mortality in patients with ischemic stroke, whereas another observational case–control study showed that irisin was significantly associated with hypertension-related stroke. Therefore, it is not yet known whether elevated irisin levels are the cause or consequence of hypertension. It is plausible that because hypertension is a disease related to systemic inflammation and oxidative stress, elevated irisin levels in hypertensive patients are part of an anti-inflammatory response against hypertension. Given that mechanisms underlying this function remain largely unknown, further studies are needed to test the hypotheses of an irisin-mediated anti-inflammatory action in hypertension.