Related Factors and Clinical Outcomes of Osteosarcopenia: A Narrative Review

Osteopenia/osteoporosis and sarcopenia are common geriatric diseases among older adults and harm activities of daily living (ADL) and quality of life (QOL). Osteosarcopenia is a unique syndrome that is a concomitant of both osteopenia/osteoporosis and sarcopenia. This review aimed to summarize the related factors and clinical outcomes of osteosarcopenia to facilitate understanding, evaluation, prevention, treatment, and further research on osteosarcopenia. We searched the literature to include meta-analyses, reviews, and clinical trials. The prevalence of osteosarcopenia among community-dwelling older adults is significantly higher in female (up to 64.3%) compared to male (8–11%). Osteosarcopenia is a risk factor for death, fractures, and falls based on longitudinal studies. However, the associations between osteosarcopenia and many other factors have been derived based on cross-sectional studies, so the causal relationship is not clear. Few studies of osteosarcopenia in hospitals have been conducted. Osteosarcopenia is a new concept and has not yet been fully researched its relationship to clinical outcomes. Longitudinal studies and high-quality interventional studies are warranted in the future.


Introduction
As the aging population grows, the number of older adults with multiple comorbidities has increased. Age-related deterioration of the structure and function of the musculoskeletal system, which is composed of bone and muscle, is common in the elderly [1,2]. The musculoskeletal system plays an important role not only in activities of daily living (ADL), such as walking, but also in metabolism [3]. Reduced functioning of the musculoskeletal system leads to falls and fractures [4] and significantly reduces ADL and quality of life (QOL) [5].
Osteopenia/osteoporosis and sarcopenia are common geriatric diseases among older adults that harm ADL and QOL. Osteopenia/osteoporosis is a condition of reduced bone the Quality Assessment of Controlled Intervention Studies [12]. This quality assessment tool consisted of 14 assessment items in each study design. We have scored these items and classified the included studies as "good," "fair," or "poor." (Supplementary Tables S1  and S2).

Osteopenia/Osteoporosis
Osteopenia/osteoporosis is diagnosed using the World Health Organization (WHO) criteria [13], and bone mineral density (BMD) is measured by dual X-ray absorptiometry (DXA). Osteopenia is defined as a BMD between −1.0 and −2.5 in standard deviations (SDs) for a young healthy adult (T-score), and osteoporosis as a BMD of −2.5 SDs or below [13]. Some studies on Japanese individuals have used the Japan Osteoporosis Society (JOS) criteria. Osteoporosis by JOS criteria is defined as a mean BMD of young adults <70% [14]. Even when the JOS criterion is used, there is little difference from the values of a T-score less than −2.5 SD as presented in the WHO criteria [14].

Sarcopenia
Sarcopenia has been defined as the presence of low muscle mass and low muscle strength and/or physical function [7]. The most widely used diagnostic criteria are the European Working Group on Sarcopenia in Older People (EWGSOP) criteria [15], updated EWGSOP criteria [16], the Asian Working Group for Sarcopenia (AWGS) criteria [17], and the updated AWGS 2019 [18]. DXA is recommended as the preferred instrument for muscle mass measurement in each criterion. When using DXA, the cut-off value for muscle mass in the updated EWGSOP criteria is 7.0 kg/m 2 for males and 5.5 kg/m 2 for females [16], and the AWGS 2019 criteria is 7.0 kg/m 2 for males and 5.4 kg/m 2 for females [18]. Muscle strength is measured by grip strength. Gait speed, the 5-time chair stand test, and the Short Physical Performance Battery (SPPB) are recommended to measure physical function [16,18].

Osteosarcopenia
Osteosarcopenia is a syndrome in which osteopenia/osteoporosis and sarcopenia coexist [9]. The criteria are not consistent, given some studies refer to osteopenia and sarcopenia, whereas others refer to osteoporosis and sarcopenia as osteosarcopenia.
Osteosarcopenic obesity is a syndrome in which osteosarcopenia and obesity coexist [19]. Definition of obesity is based on the WHO criteria of >35% body fat for women younger than 60 years [20] and >40% body fat for women aged 60 years and older [21]; for osteosarcopenic obesity [22].

Prevalence of Osteosarcopenia
The prevalence of osteosarcopenia among community-dwelling older adults is significantly higher in women compared with men. It has been reported that up to 64.3% of women had osteosarcopenia, compared with 8-11% of men among community-dwelling older adults (Table 1). Women have reduced estrogen secretion after menopause and are more likely to suffer from osteoporosis [4]. Only osteosarcopenia showed significantly reduced hand grip strength, increased chair rising time, and sit to stand power time as well as significantly increased bone turnover markers. In osteosarcopenic men, IGF1-SDS values were lower than those in control males whereas IGF1-SDS were similar in the other body compositions phenotypes in female.  Few studies of osteosarcopenia in hospitals have been conducted. Studies have been conducted only on hip fractures, liver disease, and primary biliary cholangitis (Table 2). In female hip fracture patients, the prevalence of osteosarcopenia was 28.7-65.7% [35,36]. The prevalence of osteosarcopenia in patients with liver disease was 16.8-21.8% [37,38] and 15.4% in patients with primary biliary cholangitis [39].

Osteosarcopenia as a Risk of Poor Clinical Outcomes
Osteosarcopenia is associated with many factors. Osteosarcopenia is a risk factor for death, fractures, and falls based on longitudinal studies. However, given the associations between osteosarcopenia and many other factors have been derived based on cross-sectional studies, the causal relationship is not yet clear ( Figure 1).

Osteosarcopenia as a Risk of Poor Clinical Outcomes
Osteosarcopenia is associated with many factors. Osteosarcopenia is a risk factor for death, fractures, and falls based on longitudinal studies. However, given the associations between osteosarcopenia and many other factors have been derived based on cross-sectional studies, the causal relationship is not yet clear (Figure 1).

Mortality
Osteosarcopenia is a risk factor for mortality. In a prospective observational study of 1032 community-dwelling older adults in Australia, osteosarcopenia had significantly higher 10-year mortality compared with those without sarcopenia or osteopenia (relative risk [RR] 1.49, 95% CI 1.01−2.21) [30]. Also, in a study of community-dwelling older adults in Chile, osteosarcopenia was associated with significantly higher mortality compared with those without sarcopenia or osteopenia (hazard ratio [HR] 1.81, 95% CI 1.09−2.98) [34]. In a study of hip fractures, those with osteosarcopenia had a higher risk of mortality than those with sarcopenia, osteoporosis, and normal BMD [35]. These results suggest that osteosarcopenia is a risk factor for mortality in community-dwelling older adults and patients with hip fractures.

Falls and Fractures
An association between osteosarcopenia and falls or fractures has been reported from longitudinal [28,30,34] and cross-sectional [33,24] studies. However, we must interpret osteosarcopenia carefully. Scott D et al. reported that osteosarcopenia was a risk factor for falls for 2 years and fractures for 6 years compared with those without sarcopenia and osteopenia in community-dwelling older men [28]. However, in this study, the HR for falls was higher for sarcopenia alone (HR 1.61; 95% CI 1.14−2.28) than for osteosarcopenia (HR 1.41; 95% CI 1.02−1.95). Interestingly, osteosarcopenia was not a risk factor for hip fractures (HR 1.84; 95% CI 0.60−5.61); only osteoporosis alone was a risk factor for hip

Mortality
Osteosarcopenia is a risk factor for mortality. In a prospective observational study of 1032 community-dwelling older adults in Australia, osteosarcopenia had significantly higher 10-year mortality compared with those without sarcopenia or osteopenia (relative risk [RR] 1.49, 95% CI 1.01−2.21) [30]. Also, in a study of community-dwelling older adults in Chile, osteosarcopenia was associated with significantly higher mortality compared with those without sarcopenia or osteopenia (hazard ratio [HR] 1.81, 95% CI 1.09−2.98) [34]. In a study of hip fractures, those with osteosarcopenia had a higher risk of mortality than those with sarcopenia, osteoporosis, and normal BMD [35]. These results suggest that osteosarcopenia is a risk factor for mortality in community-dwelling older adults and patients with hip fractures. The presence of sarcopenia and osteoporosis was associated with a higher spine deformity index than the presence of only one of the 2 conditions

Falls and Fractures
An association between osteosarcopenia and falls or fractures has been reported from longitudinal [28,30,34] and cross-sectional [24,33] studies. However, we must interpret osteosarcopenia carefully. Scott D et al. reported that osteosarcopenia was a risk factor for falls for 2 years and fractures for 6 years compared with those without sarcopenia and osteopenia in community-dwelling older men [28]. However, in this study, the HR for falls was higher for sarcopenia alone (HR 1.61; 95% CI 1.14−2.28) than for osteosarcopenia (HR 1.41; 95% CI 1.02−1.95). Interestingly, osteosarcopenia was not a risk factor for hip fractures (HR 1.84; 95% CI 0.60−5.61); only osteoporosis alone was a risk factor for hip fractures (HR 2.58; 95% CI 1. 22−5.45). In another prospective observational study of communitydwelling older adults, osteoporosis alone was associated with fractures over a period of 10 years (RR 1.50; 95% CI 1.07−2.10), but osteosarcopenia was not (RR 1.48; 95% CI 0.83−2.64) [30]. Thus, osteosarcopenia might not show a synergistic effect of osteoporosis and sarcopenia for predicting falls and fractures (Figure 2). The reasons for the discrepancy between the logic and evidence are not clear. Prospective, well-designed observational studies are warranted.  [30]. Thus, osteosarcopenia might not show a synergistic effect of osteoporosis and sarcopenia for predicting falls and fractures ( Figure 2). The reasons for the discrepancy between the logic and evidence are not clear. Prospective, well-designed observational studies are warranted.

Frailty
The association between frailty and osteosarcopenia has been well investigated; however, the association appears to vary depending on the definition of frailty. The frailty phenotype [41] is frequently used to define frailty and has been reported to be associated with osteosarcopenia [8,23]. An association between frailty and osteosarcopenic obesity has also been reported. Szlejf C et al. reported that frailty defined by the frailty phenotype and the Gerontopole Frailty Screening Tool were associated with osteosarcopenic obesity, but not the Fatigue, Resistance, Ambulation, Illness, and Loss of weight scale [22]. The frailty phenotype is frequently used for frailty diagnosis, and it might be a suitable diagnostic criterion for considering osteosarcopenia and osteosarcopenic obesity.

Comorbidity
An association between osteosarcopenia and chronic diseases has been reported. The associations between osteosarcopenia and peptic disease [24], inflammatory arthritis [24], diabetes (only in men) [23], and kidney dysfunction [8] have been reported. There are reports of an association between a number of chronic diseases (3 or more) [23] and osteosarcopenia. There has also been a report that high levels of HbA1c are a risk factor for osteosarcopenia [8]. Regarding the psychological aspect, depression as assessed using the Geriatric Depression Scale was associated with osteosarcopenia [24]. Osteoporosis and sarcopenia have been associated with inflammatory cytokines [10] and dietary inflammatory index scores [27], a measure of the impact of diet on inflammatory status. Hence, it is likely that chronic diseases have an impact on the development and severity of osteosarcopenia.

Frailty
The association between frailty and osteosarcopenia has been well investigated; however, the association appears to vary depending on the definition of frailty. The frailty phenotype [41] is frequently used to define frailty and has been reported to be associated with osteosarcopenia [8,23]. An association between frailty and osteosarcopenic obesity has also been reported. Szlejf C et al. reported that frailty defined by the frailty phenotype and the Gerontopole Frailty Screening Tool were associated with osteosarcopenic obesity, but not the Fatigue, Resistance, Ambulation, Illness, and Loss of weight scale [22]. The frailty phenotype is frequently used for frailty diagnosis, and it might be a suitable diagnostic criterion for considering osteosarcopenia and osteosarcopenic obesity.

Comorbidity
An association between osteosarcopenia and chronic diseases has been reported. The associations between osteosarcopenia and peptic disease [24], inflammatory arthritis [24], diabetes (only in men) [23], and kidney dysfunction [8] have been reported. There are reports of an association between a number of chronic diseases (3 or more) [23] and osteosarcopenia. There has also been a report that high levels of HbA1c are a risk factor for osteosarcopenia [8]. Regarding the psychological aspect, depression as assessed using the Geriatric Depression Scale was associated with osteosarcopenia [24]. Osteoporosis and sarcopenia have been associated with inflammatory cytokines [10] and dietary inflammatory index scores [27], a measure of the impact of diet on inflammatory status. Hence, it is likely that chronic diseases have an impact on the development and severity of osteosarcopenia.

Nutritional Status
Most studies have used body mass index (BMI) as an indicator of nutritional status. Okamura H et al. and Fahimfar N et al. reported that the risk of osteosarcopenia increases with decreasing BMI [8,32], but they did not report a clear cut-off value. Reiss J et al. reported significantly lower Mini Nutritional Assessment-Short Form scores among hospitalized elderly patients with osteosarcopenia compared with sarcopenia alone and osteoporosis alone [40]. To validate the accurate association between nutritional status and osteosarcopenia, it is necessary to use validated nutritional screening tools [42] and Global Leadership Initiative on Malnutrition criteria [43], in order to assess the risk and to diagnose undernutrition.

Physical Function
Osteosarcopenia has a negative impact on physical function. Osteosarcopenia is associated with grip strength [31], chair rising time [25], sit to stand power [25], the SPPB [33], the Timed Up and Go test [33], and the Four-Square Step test [33]. In addition, Salech F et al. reported that osteosarcopenia is a risk factor for functional limitation in community-dwelling older adults [34]. Osteosarcopenia was also associated with poorer chair rising time and sit-to-stand power, but not with sarcopenia alone or osteoporosis alone [25]. It has also been reported that osteosarcopenic obesity was associated with SPPB [22]. Given physical function is included in the diagnostic criteria for sarcopenia, a strong association between osteosarcopenia and physical function is to be expected.

Endocrine System and Bone Metabolism Marker
Endocrine factors are important physiological and pathological factors for maintaining bone and muscle structure and function [10]. In cross-sectional studies, an association between osteosarcopenia and serum parathyroid hormone [26] and insulin-like growth factor 1 [29] has been reported. In addition, an association between osteocalcin, b-crosslaps, and procollagen type 1 amino-terminal propeptide [25] and osteosarcopenia has been reported as a bone metabolism marker.

Intervention
Several randomized controlled trials (RCTs) have been conducted on communitydwelling older adults with osteosarcopenia. The first RCT examined the effects of 28 weeks of continuous high-intensity resistance training in community-dwelling osteosarcopenic men aged ≥72 years [44]. The results showed a significant positive effect on the sarcopenia Z-score (p < 0.001) in the intervention group and a significant worsening in the control group (p = 0.012). There was a significant increase in the skeletal muscle index (SMI) only in the intervention group and a significant intergroup difference in SMI and handgrip strength (both p < 0.001). The second RCT was also conducted in community-dwelling osteosarcopenic men, who received high-intensity dynamic resistance training (HIT-DRT) and whey protein supplementation for 18 months; the effects on BMD and sarcopenia parameters were examined [45]. The results showed that the effect sizes for skeletal muscle mass changes were pronounced (1.97, p < 0.001), whereas the effects for functional sarcopenia parameters were moderate (0.87, p = 0.008; handgrip strength) or low (0.39, p = 0.209; gait velocity). A third study similarly examined the impact of 12 months of low-volume HIT-DRT on BMD and SMI in men with osteosarcopenia [46]. The results showed that lumbar spine BMD was maintained in the intervention group but decreased in the control group, with a difference between groups (p < 0.001). SMI increased significantly in the intervention group but decreased significantly in the control group (both p < 0.001). Hence, resistance training alone or in combination with resistance training and protein were effective against osteoporosis or sarcopenia for community-dwelling osteosarcopenic men. However, there are no RCTs of osteosarcopenic women at this time. Because osteosarcopenia is more common in women, RCTs of osteosarcopenic women are desirable.

Call for Action
Osteosarcopenia is a new concept, and few studies have been performed on its association with clinical outcomes. In this review, we summarize the association between osteosarcopenia and clinical outcomes to facilitate its understanding, evaluation, prevention and treatment. As a result, we found several issues for clinical and research advancement in osteosarcopenia. First, we identified most of the factors of osteosarcopenia restricted crosssectional associations. Longitudinal studies for the future occurrences of osteosarcopenia and the impact of osteosarcopenia on clinical outcomes in community-dwelling older adults should lead to efficient prevention and treatment. In recent years, DXA has been widely used to assess muscle mass in community-dwelling older adults. Focusing on BMD, as well as muscle mass, can lead to research on osteosarcopenia. Second, the associations between osteosarcopenia and cognitive functioning, psychological aspects, and social skills have not yet been well examined. Given these factors have been specifically reported to be associated with sarcopenia, they could also be associated with osteosarcopenia. Third, high-quality intervention studies are needed. For women in particular, certain drugs that have been shown to be effective in treating osteoporosis could further improve clinical outcomes. Fourth, we need to aggressively conduct clinical studies in a hospital setting, given very few of these have been performed. At minimum, more studies on osteoporotic fractures (e.g., hip fractures, vertebral fracture) are warranted. Fifth, as an important step to resolve these issues, the development of a simple tool to screen for osteosarcopenia is necessary. The development of a simple screening tool can help clinical and research progress in osteosarcopenia. Finally, a meta-analysis would be required to elucidate the related factors and clinical outcomes of osteosarcopenia.

Conclusions
This review summarized the related factors and clinical outcomes of osteosarcopenia to facilitate its understanding, evaluation, prevention, treatment, and further research. Osteosarcopenia was a risk factor for fractures and falls and had cross-sectional associations with age, sex, frailty, chronic disease, physical function, nutrition, and the endocrine system. Longitudinal studies and high-quality interventional studies on elderly community-dwelling adults and hospitalized patients are warranted.
Supplementary Materials: The following are available online at https://www.mdpi.com/2072-664 3/13/2/291/s1, Table S1: Results of the quality assessment of study on osteosarcopenia and clinical outcomes. Table S2: Results of the quality assessment of study on osteosarcopenia and clinical outcomes in hospital setting.