Sarcopenia is an age-related disease, in which the muscle mass, strength, and function may decline with age [1,2]. The pathophysiology of sarcopenia is complex and results from the biological alterations in the structure of the muscles, hormonal imbalances, and external influences such as energy intake deficiencies [3]. Sarcopenia increases the risk of falls and fractures, reduces the quality of life, and increases the risk of disease and even death. It has become a major threat to the health of older adults [4-6]. Despite its seriousness, questions related to the cellular mechanisms, biomarkers, accurate diagnostic tests, and effective treatment strategies for sarcopenia remain unresolved [7].

Similar to sarcopenia, osteoporosis is an age-related disease characterized by reduced bone density, poor bone quality, and reduced bone strength with an increase in fracture risk [8,9]. Sarcopenia and osteoporosis often coexist in the fragile population, leading to significantly worse outcomes compared with those observed in either condition alone. Several studies have demonstrated considerable overlap in the pathophysiology of these two diseases, suggesting the possibility of treating these conditions together [10,11]. Since both muscles and bones are endocrine organs, the interaction between these two organs via their secretory functions has recently received special attention [12].

Sclerostin is a secreted glycoprotein expressed predominantly by mature osteocytes that serves as a negative regulator of Wnt signaling and bone formation in the human body [13]. Although the main role of sclerostin is to regulate bone mass through paracrine action, recent studies have suggested the possible endocrine effects of sclerostin on non-skeletal tissues such as adipose tissues, mineral metabolism, and vascular calcification, with the detection of sclerostin protein in the circulation [14-16]. However, few studies have demonstrated the effect of sclerostin on muscle metabolism. Therefore, we aimed to investigate the levels of serum sclerostin in older Korean adults with sarcopenia.

This study showed that serum sclerostin levels were significantly lower in Korean older adults with sarcopenia, low muscle mass, or weak muscle strength, even after considering the confounding effects of age, sex, and BMI. Serum sclerostin levels were also positively associated with muscle mass and strength. Moreover, the increase in muscle mass and strength was dose dependent according to the increase in serum sclerostin levels. Finally, the risk of sarcopenia, low muscle mass, or weak muscle strength decreased with an increase in serum sclerostin levels in Korean older adults.

Sarcopenia and osteoporosis are the most representative aging-related diseases of the musculoskeletal system caused by progressive decline in mass and strength of the muscles and bones, usually after the sixth decade of life [24,25]. Since sarcopenia and osteoporosis share common risk factors [10,26], these two disorders often co-occur and are synergistically associated with frailty, falls, fractures, hospitalizations, and mortality [27-29]. Therefore, several efforts have been made to identify the common diagnostic biomarkers and therapeutic targets in patients with both diseases [10]. In addition, more research is required to understand the biological mechanisms underlying the interaction between sarcopenia and osteoporosis.

In this context, recent in vitro studies have paid special attention to the crosstalk between muscles and bones [30]. The traditional viewpoint in the interaction between these two organs is that the mechanical forces applied to the muscles are transmitted to the skeleton to initiate bone formation [31]. Recently, both muscles and bones have been identified as secretory endocrine organs, and their secretory factors (myokines and osteokines) have shown regulatory effects on a range of tissues, including muscles and bones, through the autocrine, paracrine, and endocrine mechanisms [32]. Among various osteokines, osteocalcin and insulin-like growth factor-1 have anabolic effects on the muscles, while the receptor activator of nuclear factor kappa β ligand and fibroblast growth factor 23 showed catabolic effects [12]. However, a few studies have demonstrated the action of sclerostin, an osteocyte-secreted factor that inhibits osteoblastogenesis, on muscle metabolism, and the results have been inconsistent [33-35]. Some recent studies identified the receptors for sclerostin (low-density lipoprotein receptor-related protein complex [LRP5/6]) in muscle cells [33] and demonstrated that the secretome of osteocytes inhibits skeletal muscle cell differentiation [34]. However, in an animal model of spinal cord injury, sclerostin antibody did not slow the muscle atrophy, unlike the expected action of sclerostin as an inhibitor of muscle hypertrophy [35]. Moreover, some in vitro and ex vivo evidence suggests that the osteocytes in culture can stimulate myogenesis and contractile function [36]. Albeit the effect of osteocyte-derived sclerostin on muscle metabolism has not reached a conclusion so far, reports of recent studies suggested the possibility of the close interaction between muscle and bone via sclerostin. In this regard, the significantly decreased levels of serum sclerostin in Korean older adults with sarcopenia in our study provides additional clinical evidence to this interaction and shows the possible role of circulatory sclerostin as a biomarker for both sarcopenia and osteoporosis.

However, the decreased levels of serum sclerostin in our study participants with sarcopenia suggested a contrary anabolic role of circulatory sclerostin in the muscles compared with its known catabolic role in the bones. Although the reason for our counterintuitive finding remains unclear, some explanations could be inferred from the change in serum sclerostin levels according to bone strength in previous studies [37]. In previous in vitro and in vivo studies, higher mechanical loading in the bone was associated with lower serum sclerostin secretion, which may reflect the compensatory adaptation of osteocytes to existing bone strains [38,39]. These findings suggest that individuals with lower bone strength may have higher mechanical strains in the remaining bone, resulting in a decrease in sclerostin expression to compensate for bone fragility. Accordingly, a previous Korean study reported that low serum sclerostin levels were associated with a high prevalence of osteoporotic fractures and low bone mineral density values [40]. Moreover, the muscles can protect bone loading, and their ability to attenuate loads is compromised when the muscles are dysfunctional [31,41]. Therefore, individuals with weakened muscle may have higher bone strain, which also results in compensatory adaptation of osteocytes as the sclerostin secretion decreased. On the contrary, a previous clinical study investigating the association between serum sclerostin levels and muscle mass in middle-aged or older adults showed that serum sclerostin levels increased in individuals with low muscle mass [42]. However, this inverse association between muscle-related parameters and serum sclerostin levels was only limited to muscle mass in that study, while our study demonstrated consistent positive associations of muscle mass and strength with serum sclerostin levels. Finally, a recent study demonstrated that skeletal muscle is a new source of sclerostin [43]. In this study, sclerostin was expressed in the myogenic cell lines at all stages of differentiation. In mice, the expression of sclerostin was dynamically modulated in a muscle-specific manner throughout the lifespan and showed a decreasing trend in older mice. Therefore, the decrease in serum sclerostin levels in sarcopenic individuals in our study might reflect the decrease in muscle cell-secreted sclerostin according to the muscle mass.

These hypotheses for lower serum sclerostin levels in older sarcopenic adults point to the potential involvement of sclerostin secreted from bone and muscle as a biomarker and therapeutic target for sarcopenia. Moreover, recent clinical trials proving the efficacy of romosozumab, a monoclonal antibody against sclerostin, on fracture risk in postmenopausal women revealed that romosozumab also tended to reduce the risk of falls [44- 46]. Because frail people often have weak muscles, there is a possibility that fewer falls with romosozumab administration could be attributable to muscle anabolic effects of this drug. Further clinical studies assessing the roles of romosozumab on muscle mass and strength will give more insight into the potential of sclerostin inhibition as a sarcopenia treatment target.

Our study has several strengths. First, our study included various structural and functional parameters of muscle health, including muscle mass, grip strength, gait speed, time to complete five chair stands, SPPB score, and SPS, which contributed to the greater reliability of the results. Second, the Asian-specific cutoff point was adopted for the diagnosis of sarcopenia [22], because the muscle parameters may vary depending on ethnicity, body size, lifestyle, and cultural background. However, this study has several limitations. First, this observational study could not determine the causal relationship between the variables. Second, our study population was exclusively South Korean; therefore, whether our results are applicable to other populations remains uncertain. Third, various confounding factors could not be considered in the multivariate analyses due to the relatively small sample size. Finally, our bioelectrical impedance analysis methodology might not provide valid estimates of the total body water when hydration states are altered, potentially leading to errors in muscle mass assessments. Finally, only the serum sclerostin levels were measured in our study. Since recent evidence suggests the presence of sclerostin in muscle tissue, measurement of muscle-specific sclerostin will provide a more plausible association between circulatory sclerostin and muscle-related parameters.

In conclusion, our study showed that higher serum sclerostin levels were associated with a lower risk of sarcopenia, low muscle mass, and weak muscle strength in Korean older adults. Therefore, serum sclerostin levels may be a biomarker for muscle health, and further in vitro research investigating the role of sclerostin in muscle metabolism, especially in relation to the bone, may provide new therapeutic targets for both sarcopenia and osteoporosis.