Relationship between Osteosarcopenia and Frailty in Patients with Chronic Liver Disease

Osteosarcopenia and frailty have a negative health impact on an aging society. This cross-sectional study aimed to investigate the clinical characteristics and relationship of osteosarcopenia and frailty in 291 patients with chronic liver disease (CLD), who comprised 137 males and 154 females, with a median age of 70.0 years. Sarcopenia was diagnosed according to the Japan Society of Hepatology criteria. Bone mineral density was measured using dual-energy X-ray absorptiometry. Frailty was defined by five parameters (exhaustion, slowness, weakness, low physical activity, and weight loss). Among the 291 patients, 49 (16.8%) and 81 (27.8%) had osteosarcopenia and frailty, respectively. Frailty and vertebral fracture were more frequently noted in patients with osteosarcopenia than in those without osteosarcopenia (79.6% vs. 17.4% and 59.2% vs. 20.2%, respectively; p < 0.001 for both). Meanwhile, osteosarcopenia and vertebral fracture were more frequently observed in patients with frailty than in those without frailty (48.1% vs. 4.8% and 49.4% vs. 18.1%, respectively; p < 0.001 for both). On multivariate analysis, frailty was an independent factor associated with osteosarcopenia (odds ratio (OR), 9.837; p < 0.001), and vice versa (OR, 10.069; p < 0.001). Osteosarcopenia and frailty were prevalent, closely interrelated, and increased the risk of vertebral fracture in patients with CLD.


Introduction
Osteoporosis and sarcopenia are musculoskeletal disorders characterized by the loss of bone mass and skeletal muscle mass and strength, respectively [1][2][3][4][5]. Although both these disorders affect different organs and tissues, they are closely interrelated through common factors, such as genetic properties, endocrine hormones, nutrition conditions, and lifestyle behavior [2,6]. Accordingly, the concept and term "osteosarcopenia" have been established recently, which is defined as the concomitant occurrence of sarcopenia and osteoporosis [1][2][3][4]. Osteosarcopenia has a negative impact on health-related quality of life and eventual prognosis, with an increased risk of falls, fractures, institutionalization, and mortality [1][2][3][4]. Recently, we reported a relatively high prevalence of osteosarcopenia in 21.8% of patients with liver cirrhosis (LC), and a close association between osteosarcopenia and vertebral criteria proposed by the Japan Society of Hepatology [21]. Briefly, sarcopenia is defined as having low handgrip strength (<26 kg for males and <18 kg for females) and low muscle mass (SMI < 7.0 kg/m 2 for males and <5.7 kg/m 2 for females). Pre-sarcopenia and dynapenia were defined as having low muscle mass without low muscle strength and having low muscle strength without low muscle mass, respectively. SMI was calculated as the sum of the muscle mass of the four limbs divided by the height in square meters (kg/m 2 ). Gait speed was assessed over a distance of 6 m, and low gait speed was defined as < 1.0 m/s. Frailty was diagnosed using a validated screening tool based on Fried's five components [19,22]: weight loss (≥2 kg over the last 6 months); weakness (handgrip strength < 26 kg for males and < 18 kg for females); exhaustion (positive answer to the question: "In the last two weeks, have you felt tired without a reason?"); slowness (gait speed < 1.0 m/s); low physical activity (negative answer to the following two questions: "Do you engage in moderate levels of physical exercise or sports aimed at health?" and "Do you engage in low levels of physical exercise aimed at health?"). Absence of these five components was defined as non-frailty, presence of 1-2 components was defined as pre-frailty, and presence of ≥3 components defined as frailty [22].

Statistical Analysis
Continuous variables are presented as medians and interquartile ranges in parentheses. The Mann-Whitney U test was used to evaluate differences in the distribution of continuous variables between two groups, while the Kruskal-Wallis test followed by the Steel-Dwass post-hoc test was used for multiple comparisons among three or four groups. Categorical variables are presented as numbers and percentages in parentheses. Inter-group differences were evaluated using the chi-squared test. Univariate and multivariate logistic regression analyses were performed to identify variables that were significantly and independently associated with osteosarcopenia and frailty. Statistical analyses were performed using SPSS (version 26, IBM, Armonk, NY, USA), with a p-Value < 0.05 indicating statistical significance.

Patient Characteristics
Baseline clinical characteristics of the 291 patients with CLD enrolled in the current study are shown in Table 1

Comparison of Clinical Characteristics between Patients with and without Osteosarcopenia
Males accounted for 32.7% of the osteosarcopenia group and 50.0% of the non-osteosarcopenia group, with osteosarcopenia being more prevalent in females than in males (p = 0.027; Table 1). Osteosarcopenia patients were older (p < 0.001) and had a lower body mass index (BMI; p < 0.001) as compared to non-osteosarcopenia patients. Regarding biochemical parameters, the osteosarcopenia group had significantly lower levels of IGF-1 (p < 0.001) and BCAA (p < 0.001), and higher levels of M2BPGi (p = 0.030) and PTH (p = 0.010) as compared to the non-osteosarcopenia group. Notably, the osteosarcopenia group showed a significantly higher prevalence of frailty (79.6% vs. 17.4%), low gait speed (79.6% vs. 23.1%), and vertebral fracture (59.2% vs. 20.2%) than the non-osteosarcopenia group (p < 0.001 for all).

Comparison of Clinical Characteristics between Patients with and without Osteosarcopenia
Males accounted for 32.7% of the osteosarcopenia group and 50.0% of the non-osteosarcopenia group, with osteosarcopenia being more prevalent in females than in males (p = 0.027; Table 1). Osteosarcopenia patients were older (p < 0.001) and had a lower body mass index (BMI; p < 0.001) as compared to non-osteosarcopenia patients. Regarding biochemical parameters, the osteosarcopenia group had significantly lower levels of IGF-1 (p < 0.001) and BCAA (p < 0.001), and higher levels of M2BPGi (p = 0.030) and PTH (p = 0.010) as compared to the non-osteosarcopenia group. Notably, the osteosarcopenia group showed a significantly higher prevalence of frailty (79.6% vs. 17.4%), low gait speed (79.6% vs. 23.1%), and vertebral fracture (59.2% vs. 20.2%) than the non-osteosarcopenia group (p < 0.001 for all).

Factors Associated with Osteosarcopenia in Patients with Chronic Liver Disease
The following eight variables showed a significant relation with osteosarcopenia on univariate analysis: gender, age, BMI, IGF-1, BCAA, PTH, frailty, and vertebral fractures (Table S2). On

Factors Associated with Osteosarcopenia in Patients with Chronic Liver Disease
The following eight variables showed a significant relation with osteosarcopenia on univariate analysis: gender, age, BMI, IGF-1, BCAA, PTH, frailty, and vertebral fractures (Table S2). On multivariate analysis, the following five variables were retained as independent factors associated with osteosarcopenia ( Table 2)

Discussion
Osteosarcopenia, a recently established syndrome, is defined by the coexistence of sarcopenia and osteoporosis. It has now become a global health concern, given that both of the disease conditions are risk factors for falls, disability, hospitalization, and mortality [1][2][3][4]. In the present study, the prevalence of osteosarcopenia was 16.8% among all patients with CLD and increased to 48.1% when limited to those with frailty (median, 76 years), whereas it was only 4.8% among those without frailty (median, 67 years). A community-based geriatric study of Chinese elders reported the prevalence of 33.3% of osteosarcopenia among frail elders (mean, 83-84 years) and 1.7% among non-frail elders (mean, 72-74 years) [18]. These findings indicate that individuals with frailty are more susceptible to osteosarcopenia, irrespective of the presence of CLD. Intriguingly, our study cohort was younger than the Chinese elderly cohort, and osteosarcopenia was more frequently noted in the former than in the latter; thus suggesting that CLD patients with frailty are more vulnerable to osteosarcopenia than the general population with frailty. In the present study, we found that frailty was most frequently noted in the osteosarcopenia group, and it was significantly and independently associated with osteosarcopenia. Therefore, early diagnosis and appropriate treatment for osteosarcopenia are required, especially in CLD patients with frailty.
Frailty is a complex syndrome characterized by a decline in multisystem functioning and physiologic reserve, combined with increased vulnerability to stressors, and an increase in the incidence of falls, disability, hospitalization, and mortality among elders and patients with advanced liver disease [8][9][10][11][12][13][14][15]. Despite advances in clinical research on frailty in patients with end-stage liver disease, the prevalence of frailty among those with CLD at different disease stages and its etiologies has not been fully elucidated. In the present study, we found that the prevalence of frailty was 27.8% among 291 patients with CLD, including four patients with end-stage liver disease. Meanwhile, the prevalence of frailty among community-dwelling elders was 5.6% in Japan and 14.2% in China [17,18]. These differences suggest that patients with CLD are more susceptible to frailty as compared to the general population. Our findings showed that (1) the frail group had significantly lower levels of SMI, handgrip strength, and BMD as compared to the non-frail and pre-frail groups; (2) osteosarcopenia occurred more frequently in the frail group as compared to the other groups; (3) frailty not only occurred more frequently in the osteosarcopenia group, but also showed a significant and independent association with osteosarcopenia; (4) conversely, osteosarcopenia was a significant, independent factor associated with frailty. A geriatric cross-sectional study from China showed that the likelihood of frailty was substantially higher among community-dwelling elders with osteosarcopenia [18]. A 4-year observational geriatric study from Japan reported that the occurrence of frailty significantly increased with an increased incidence of osteosarcopenia [17]. These findings indicate that osteosarcopenia and frailty are closely interrelated with each other. The present study is the first to demonstrate the relationship between osteosarcopenia and frailty in patients with CLD.
Muscle mass and bone mass are closely interrelated during growth [23]. Several factors (such as genetic predisposition, endocrine imbalance, nutritional states, and inflammation) can influence muscle tissues and bone metabolism. In the present study, we found that decreases in IGF-1 and BCAA were associated with osteosarcopenia and frailty. IGF-1, produced primarily in hepatocytes and some tissues (including bone and muscle), is involved in muscle protein synthesis and bone remodeling and the maintenance of bone mass and strength due to its stimulation of osteoblast differentiation and proliferation [23,24]. BCAAs, especially leucine, contribute to protein synthesis through the mammalian target of rapamycin pathway [25]. Given that the liver is a central organ for nutrient metabolism, LC is complicated by protein energy malnutrition and hyperammonemia and can lead to the consumption of BCAA by skeletal muscles for energy production and ammonia metabolism [26]. A reduced concentration of systemic BCAA is associated with sarcopenia in older adults and patients with LC [7,27]. Furthermore, frail participants showed lower daily consumption of protein and BCAA compared to both pre-frail and robust individuals [28]. Thus, our results are theoretically reasonable and support the notion that decreased levels of both IGF-1 and BCAA are associated with the development of osteosarcopenia and frailty in patients with CLD.
In the present study, both osteosarcopenia and frailty were closely associated with vertebral fractures and impaired physical performance in patients with CLD. Among community-dwelling elders, osteosarcopenia can greatly impair physical performance and balance, as well as increase the risk of falls and fractures, as compared to non-osteosarcopenia, sarcopenia, and osteoporosis alone [29,30]. Furthermore, vertebral fractures cause impairment in physical function and immobility [31], which can lead to a loss of muscle as well as bone mass and strength. In general, physical activity is essential for maintaining and improving BMD, muscle strength, and quality of the bone and muscle [32]. Multicomponent exercise interventions, combining resistance training with aerobic, balance and flexibility exercises, could be effective strategies in improving the muscle strength, gait speed, balance, and physical performance, and consequently reduce the fear of falling [33,34]. Pharmacologic treatment for osteosarcopenia remains to be developed; however, denosumab, a receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor, was recently reported to improve not only BMD but also muscle mass and strength in postmenopausal women with osteoporosis [35]. Large-scale studies should be conducted in the future to determine the optimal exercise and pharmacological treatment strategies for improving the functional and health-related outcomes in CLD patients with osteosarcopenia and/or frailty.
This cross-sectional study had some limitations. First, nutritional intake was not assessed. Second, the daily physical activity was not evaluated in detail. Third, we did not assess if osteosarcopenia preceded and/or initiated or facilitated frailty and vice versa, over a long-term observation period. Lastly, we did not evaluate if steroid therapy affected osteosarcopenia and frailty, although this study cohort included 7 patients who had been receiving prednisolone treatment for autoimmune hepatitis. A large-scale study that includes these assessments is needed to resolve the challenges related to osteosarcopenia and frailty in patients with CLD.

Conclusions
In the present study, we demonstrated that osteosarcopenia and frailty are prevalent and closely interrelated in patients with CLD. Specifically, patients with osteosarcopenia and/or frailty are susceptible to vertebral fractures that can lead to impairment in physical function. Therefore, comprehensive diagnostic assessments and appropriate treatment for these complications are crucial in patients with CLD.