Sharing Circulating Micro-RNAs between Osteoporosis and Sarcopenia: A Systematic Review

Simple Summary Osteoporosis and sarcopenia are common geriatric syndromes among the elderly population. Their coexistence was recently defined as osteosarcopenia, showing an incidence of ~37% in older adults, thus posing a serious global health burden. Thus, the search for osteosarcopenia biomarkers is mandatory for the early detection and prevention of deterioration of the condition. In this context, circulating microRNAs (miRs) show promise as advanced biomarkers. Here, we carried out a systematic review to explore and analyze the potential clinical biomarker utility of circulating miRs (serum, plasma, blood) shared between osteoporosis/osteopenia and sarcopenia. Abstract Background: Osteosarcopenia, a combination of osteopenia/osteoporosis and sarcopenia, is a common condition among older adults. While numerous studies and meta-analyses have been conducted on osteoporosis biomarkers, biomarker utility in osteosarcopenia still lacks evidence. Here, we carried out a systematic review to explore and analyze the potential clinical of circulating microRNAs (miRs) shared between osteoporosis/osteopenia and sarcopenia. Methods: We performed a systematic review on PubMed, Scopus, and Embase for differentially expressed miRs (p-value < 0.05) in (i) osteoporosis and (ii) sarcopenia. Following screening for title and abstract and deduplication, 83 studies on osteoporosis and 11 on sarcopenia were identified for full-text screening. Full-text screening identified 54 studies on osteoporosis, 4 on sarcopenia, and 1 on both osteoporosis and sarcopenia. Results: A total of 69 miRs were identified for osteoporosis and 14 for sarcopenia. There were 9 shared miRs, with evidence of dysregulation (up- or down-regulation), in both osteoporosis and sarcopenia: miR-23a-3p, miR-29a, miR-93, miR-133a and b, miR-155, miR-206, miR-208, miR-222, and miR-328, with functions and targets implicated in the pathogenesis of osteosarcopenia. However, there was little agreement in the results across studies and insufficient data for miRs in sarcopenia, and only three miRs, miR-155, miR-206, and miR-328, showed the same direction of dysregulation (down-regulation) in both osteoporosis and sarcopenia. Additionally, for most identified miRs there has been no replication by more than one study, and this is particularly true for all miRs analyzed in sarcopenia. The study quality was typically rated intermediate/high risk of bias. The large heterogeneity of the studies made it impossible to perform a meta-analysis. Conclusions: The findings of this review are particularly novel, as miRs have not yet been explored in the context of osteosarcopenia. The dysregulation of miRs identified in this review may provide important clues to better understand the pathogenesis of osteosarcopenia, while also laying the foundations for further studies to lead to effective screening, monitoring, or treatment strategies.


Introduction
Worldwide, the population of people over the age of 60 is expected to grow from 841 million in 2013 to more than 2 billion by 2050, with a percentage increase from nucleotides that work as post-transcriptional regulators of protein-coding genes and the non-coding genome [21]. They are key molecular regulators in cells, which modify the expression of genes at a post-transcriptional level by impeding the translation of specific mRNAs or inducing specific mRNA degradation [21]. Significantly, mature miRs can exit cells and are detected in the bloodstream [20][21][22][23]. In 2008, two different research teams discovered and analyzed the presence of miRs in the bloodstream, and since then, various sequences have been found in human-and animal-derived plasma and serum [20][21][22][23]. However, to date, most miR studies have been conducted using cultured cells or animal model systems, and only a small number of studies have investigated changes in circulating miRs in pathological conditions such as osteoporosis and sarcopenia. Thus, considering the increasing prevalence of osteosarcopenia, the search for specific shared miRs between osteoporosis and sarcopenia should be considered mandatory for the early detection of the condition. The objective of this systematic review was to explore and analyze the potential clinical biomarker utility of circulating miRs (serum, plasma, blood) that are shared between osteoporosis/osteopenia and sarcopenia. To the best of our knowledge, there is no previous systematic review assessing shared miR between osteoporosis/osteopenia and sarcopenia.

Eligibility Criteria
The PICOS model (Population, Intervention, Comparison, Outcomes, Study design) was used to design this study: (1) studies that considered osteoporotic/osteopenic and sarcopenic patients (Population), submitted or not (2) to a specific surgical intervention (Interventions), (3) with or without a comparison group (healthy controls) (Comparisons), (4) that reported significant differences (p < 0.05) on specific circulating miRs (Outcomes), in (5) clinical studies (Study design). Studies from 2 January 2013 to 2 January 2023 were included in this review if they met the PICOS criteria. We excluded studies that evaluated (1) miRs in cells or animal model systems; (2) miRs in patients with other concomitant severe pathological conditions (e.g., cancer, metastases, diabetes, HIV, mastocytosis, thyroid pathologies, arthritis, acromegaly, ulcerative colitis, chronic heart failure, idiopathic and genetic osteoporosis, cerebral diseases) in addition to osteoporosis and sarcopenia; (3) miRs as modulators of drug resistance, in drug response and/or as drugs for medical intervention; (4) miRs for the constuction of mathematical modeling tools; (5) miRs varia- However, in contrast to osteoporosis and sarcopenia considered individually, to date, few data are available on osteosarcopenia. What is already known is that, considering the clinical outcomes linked with both osteoporosis and sarcopenia, the diagnosis of osteosarcopenia syndrome is mandatory for enabling clinical care [12]. The clinical diagnosis is hampered by three principal key difficulties in the evaluation of muscle and bone status [13,14]. First, despite imaging modalities such as dual-energy X-ray absorptiometry (DXA), magnetic resonance imaging (MRI), and computed tomography (CT) being able to provide an objective and appropriately estimation of body composition [13], these procedures are technically complex and commonly only available in well-equipped medical institutions. The use of bioelectrical impedance analysis (BIA), a potential tool for sarcopenia assessment, is of limited use in elderly individuals, since measured muscle mass may be underestimated due to inadequate hydration in aging populations [14]. Second, the repeatability of the estimation methods is inadequate. The main assessments for muscle function include usual gait speed and a short physical performance battery (SPPB) [14]. Third, osteoporosis and sarcopenia are chronic and multifactorial diseases, and not all individuals present the same rates of muscle and bone loss. Therefore, resultant indicators to track progression over time or response to specific interventions are critical.
To overcome the absence of 'gold standard' techniques to correctly evaluate muscle and bone, several circulating biomarkers have been explored based on the molecular biological mechanisms of their involvement in the pathogenesis of sarcopenia and osteoporosis. Over the past few decades, a novel kind of RNA, microRNAs (miRs), have attracted great attention from researchers and clinicians as alternative and advanced biomarkers for numerous pathological conditions, leading to the conclusion that miRs are "fingerprints" for specific diseases [15][16][17][18][19][20]. MiRs are short, non-coding RNAs of typically 18-22 nucleotides that work as post-transcriptional regulators of protein-coding genes and the non-coding genome [21]. They are key molecular regulators in cells, which modify the expression of genes at a post-transcriptional level by impeding the translation of specific mRNAs or inducing specific mRNA degradation [21]. Significantly, mature miRs can exit cells and are detected in the bloodstream [20][21][22][23]. In 2008, two different research teams discovered and analyzed the presence of miRs in the bloodstream, and since then, various sequences have been found in human-and animal-derived plasma and serum [20][21][22][23]. However, to date, most miR studies have been conducted using cultured cells or animal model systems, and only a small number of studies have investigated changes in circulating miRs in pathological conditions such as osteoporosis and sarcopenia. Thus, considering the increasing prevalence of osteosarcopenia, the search for specific shared miRs between osteoporosis and sarcopenia should be considered mandatory for the early detection of the condition. The objective of this systematic review was to explore and analyze the potential clinical biomarker utility of circulating miRs (serum, plasma, blood) that are shared between osteoporosis/osteopenia and sarcopenia. To the best of our knowledge, there is no previous systematic review assessing shared miR between osteoporosis/osteopenia and sarcopenia.

Eligibility Criteria
The PICOS model (Population, Intervention, Comparison, Outcomes, Study design) was used to design this study: (1) studies that considered osteoporotic/osteopenic and sarcopenic patients (Population), submitted or not (2) to a specific surgical intervention (Interventions), (3) with or without a comparison group (healthy controls) (Comparisons), (4) that reported significant differences (p < 0.05) on specific circulating miRs (Outcomes), in (5) clinical studies (Study design). Studies from 2 January 2013 to 2 January 2023 were included in this review if they met the PICOS criteria. We excluded studies that evaluated (1) miRs in cells or animal model systems; (2) miRs in patients with other concomitant severe pathological conditions (e.g., cancer, metastases, diabetes, HIV, mastocytosis, thyroid pathologies, arthritis, acromegaly, ulcerative colitis, chronic heart failure, idiopathic and genetic osteoporosis, cerebral diseases) in addition to osteoporosis and sarcopenia; (3) miRs as modulators of drug resistance, in drug response and/or as drugs for medical intervention; (4) miRs for the constuction of mathematical modeling tools; (5) miRs variation in physical activity; (6) miRs transfection in cells; (7) miRs expression profiles in exosomes; (8) articles with incomplete outcomes or data. Additionally, we excluded reviews, letters, comments to editor, meta-analysis, editorials, protocols and recommendations, guidelines, and articles not written in English.

Search Strategies
Our literature review involved a systematic search conducted in January 2023. We performed our review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [24]. The search was carried out on three databases: PubMed, Scopus, and Embase. The following combination of terms was used: (osteoporo-Life 2023, 13, 602 4 of 40 sis) AND ((serum miR) OR (circulating miR)) and (sarcopenia) AND ((serum miR) OR (circulating miR)); for each of these terms, free words, and controlled vocabulary specific to each bibliographic database were combined using the operator "OR". The combination of free-vocabulary and/or Medical Subject Headings (MeSH) terms for the identification of studies in PubMed, Scopus, and Embase are reported in Table 1.

Selection Process
After submitting the articles to a public reference manager (Mendeley Desktop 1.19.8) to eliminate duplicates, possible relevant articles were screened using title and abstract by two reviewers (FS and DC). Studies that did not meet the inclusion criteria were excluded from review, and any disagreement was resolved through discussion until a consensus was reached or with the involvement of a third reviewer (GG). Subsequently, the remaining studies were included in the final stage of data extraction.

Data Collection Process and Synthesis Methods
The data extraction and synthesis process started with cataloging study details. To increase validity and avoid omitting potentially findings for the synthesis, two authors (FS and DC) extracted and constructed the tables (Tables 2-5) while taking into consideration demographics data (country of publication, study design, patients number, ethnicity, sex/age, comorbidities, osteoporosis or sarcopenia diagnostic measures) and methodology of studies on osteoporosis and sarcopenia (miR, miR assay, tissue, endogenous genes, technical replicates, timing of sample collection, miR direction in osteoporosis or sarcopenia, main results).

Study Selection and Characteristics
The initial literature search retrieved 486 studies. Of those, 430 studies (136 from PubMed, 189 from Scopus, 105 from Embase) were on osteoporosis and 56 were on sarcopenia (20 from PubMed, 24 from Scopus, 12 from Embase). Articles were screened for title and abstract, and 194 articles were selected: 173 for osteoporosis and 21 for sarcopenia. Subsequently, these articles were submitted to a public reference manager to eliminate duplicates. The resulting 94 complete articles, 83 on osteoporosis and 11 on sarcopenia, were then reviewed to establish whether the publications met the inclusion criteria, and 58 (53 on osteoporosis, 4 on sarcopenia, and 1 on both osteoporosis and sarcopenia) studies were considered eligible for this review. The search strategy and study inclusion and exclusion criteria are detailed in Figure 2.
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Study Selection and Characteristics
The initial literature search retrieved 486 studies. Of those, 430 studies (136 from Pub-Med, 189 from Scopus, 105 from Embase) were on osteoporosis and 56 were on sarcopenia (20 from PubMed, 24 from Scopus, 12 from Embase). Articles were screened for title and abstract, and 194 articles were selected: 173 for osteoporosis and 21 for sarcopenia. Subsequently, these articles were submitted to a public reference manager to eliminate duplicates. The resulting 94 complete articles, 83 on osteoporosis and 11 on sarcopenia, were then reviewed to establish whether the publications met the inclusion criteria, and 58 (53 on osteoporosis, 4 on sarcopenia, and 1 on both osteoporosis and sarcopenia) studies were considered eligible for this review. The search strategy and study inclusion and exclusion criteria are detailed in Figure 2.

Study General Characteristics
Tables 2 and 4 describe the study demographics characteristics respectively for osteoporosis and sarcopenia. Most studies (69%) on osteoporosis do not define the study design; studies where the types of cohorts are specified are prospective (n = 10), case-control, and/or cross-sectional (n = 6) and retrospective (n = 1). None of the studies on sarcopenia

miRs Dysregulation in Osteoporosis and Sarcopenia
As reported in Tables 4 and 5, differential miRs expression is defined as an alteration, i.e., up-or down-regulation, both in osteoporosis/osteopenia and sarcopenia versus healthy controls, including statistically significant p-values < 0.05. In studies that reported a discovery phase and validation phase, only miRs confirmed in the validation phase were considered for this review.
For miR-21, not all studies agreed on direction of expression, with four studies reporting up-regulation [32,54,59,75] and 3 down-regulation [42,70,78] in the osteoporotic groups compared to the non-osteoporotic groups. MiR-21 up-regulation and down-regulation was described also for osteoporotic fracture patients [54,75,78]. The study by Li et al. [42] also showed down-regulation of miR-21 in plasma from osteopenic patients; a Greek study [70] showed downregulation of miR-21 and miR-21-5p in serum of patients with low BMD and vertebral fracture in comparison to patients with low BMD and no fracture.
MiR-23a and its -3p form were up-regulated in four studies [32,57,59,75] and downregulated in two studies [34,70]. Ciuffi et al. [34], in their prospective multicenter study, measured miRs by using a next-generation sequencing -based prescreening profile approach considering not only female patients but also osteopenic and/or osteoporosis male patients, showing the deregulated serum levels of miR-23a-3p in osteoporotic patients as well as their relationship with bone quality parameters and sensitivity/specificity in distinguishing osteoporotic patients from normal BMD subjects. Yavropoulou et al. [70] also showed deregulated serum level of miR-23a in patients with low bone mass compared with healthy controls. Differently, up-regulation of miR-23a was associated with BMD variation and vertebral fracture in other studies [32,57,59,75].
Concerning miR-122 [26,50,54,59,64] and miR-125 [30,32,54,59,64], their expression level in the different studies were conflicting for direction of regulation. In 3/5 studies, miR-122 was upregulated [54,59,64] in osteoporotic patients versus healthy controls, while in the remaining studies [26,50], it was downregulated. In particular, Mandourah et al. [50] showed that miR-122 was significantly differentially expressed between non-osteoporotic controls, osteopenic, and osteoporotic patients. Concerning miR-125b, it was overexpressed in almost all the studies (4/5), except for the study by Chen et al. [32], wherein a downregulation in the osteoporotic group compared to the non-osteoporotic group was seen. A similar trend was seen also for miR-30 [29,30,60,76] that resulted in overexpression in 3/4 studies. Only one study, by Chen et al. [29], revealed that miR-30b-5p was significantly down-regulated in postmenopausal women with osteopenia or osteoporosis. In contrast, miR-27a and its -3p form was down-regulated in postmenopausal women with osteoporosis in comparison to healthy controls in almost all the studies [37,72] and up-regulated in only one study [64].

Sharing miRs between Osteoporosis and Sarcopenia
Between osteoporosis and sarcopenia, there was a moderate degree of overlap of dysregulated miRs. Specifically, nine shared miRs between osteoporosis and sarcopenia were detected in this review: miR-206, miR-208, miR-222, miR-328, miR-93, miR-155, miR-23a-3p, miR-29a, and miR-133a and b (Figure 3). However, for most of these miRs, there has been no replication by more than one study, and this is particularly true for all Life 2023, 13, 602 32 of 40 miRs analyzed in sarcopenia. In contrast, for osteoporosis, miR-222, miR-23a, and miR-133a or b were respectively found in five, four and three studies.

Sharing miRs between Osteoporosis and Sarcopenia
Between osteoporosis and sarcopenia, there was a moderate degree of overlap of dysregulated miRs. Specifically, nine shared miRs between osteoporosis and sarcopenia were detected in this review: miR-206, miR-208, miR-222, miR-328, miR-93, miR-155, miR-23a-3p, miR-29a, and miR-133a and b (Figure 3). However, for most of these miRs, there has been no replication by more than one study, and this is particularly true for all miRs analyzed in sarcopenia. In contrast, for osteoporosis, miR-222, miR-23a, and miR-133a or b were respectively found in five, four and three studies.

Risk of Bias Assessment
More than 60% of the studies on osteoporosis included in the current systematic review satisfied most of the items in the QUADAS2, which suggests that the overall quality of included studies was moderate-to-high (Table 6). Six studies showed a high risk of bias in the patient selection [29,32,39,46,53,76] by not reporting, beyond the type of study, the allocation of the number of patients in the different experimental groups. Concerning the index text and how it was conducted and/or interpreted, most of the included studies showed a low risk of bias. However, several studies did not specify the endogenous control used to perform the qRT-PCR, and thus they were scored to have a high risk of bias in relation to the index test [29,33,35,37,39,53,57,62,64,67,69,74,76,79]. The reference standard and the flow and timing risk of bias were low in all the examined studies.
All the studies on sarcopenia [32,[81][82][83] satisfied all the items in the QUADAS2, which suggests that the overall quality of the included studies was high. Table 6. Summary of risk-of-bias assessment (QUADAS-2 tool). Green: low risk of bias or low concern in applicability. Orange: unclear risk. Red: high risk of bias or high concern in applicability. The assessment is weighted based on the sample size in each study.

Discussion
Osteosarcopenia is a complex and multifactorial disabling disease that is characterized by decreasing bone and muscle mass that is often followed by low-traumatic fracture occurrences and muscle atrophy with a strong negative impact on the quality of life and important socio-economic repercussions [8][9][10][11]. The availability of valid diagnostic tools to identify the onset, progression, and manifestation of osteoporosis has allowed physicians to manage the pathological condition more effectively. However, osteoporosis tools are not yet able to guarantee the necessary sensitivity and specificity [13,14]. Concerning sarcopenia, because of confused definitions and inaccurate screening tools, it frequently remains undiagnosed [13,14]. Osteosarcopenia, which identifies the concomitant presence of sarcopenia and osteoporosis, does not have a unique model of diagnosis but is based on the reference definitions of osteoporosis and sarcopenia, which at present still have limitations. However, if a diagnosis of sarcopenia according to the indications of EWGSOP2 is present, a low bone mass determined by the T-score BMD confirms a diagnosis of osteosarcopenia [8]. This diagnostic criterion was further confirmed by Tarantino et al. in a recent meta-analysis that identified a new potential predictive model based on the correlation of T-score and handgrip strength. The results of this study confirmed how the trend of these variables goes hand-in-hand with the progressive increase in the severity of the osteoporotic and sarcopenic condition, up to osteosarcopenia [84]. However, in addition to imaging modalities and tools for osteosarcopenia diagnosis, the biochemical assessment of bone and muscle metabolism has been also proposed to improve early diagnosis and screening. Furthermore, in recent years, the scientific community has focused its attention on a novel class of potential diagnostic biomarkers, both for osteoporosis and sarcopenia, named circulating cell-free miRs [15][16][17][18][19][20]. Several studies have shown that miRs in cultured cells or animal models may play pivotal roles in osteoporosis and sarcopenia, but fewer data are available on circulating miRs [15][16][17][18][19][20][21]. Thus, given the increasing prevalence of osteosarcopenia in elderly populations, we systematically evaluated the potential clinical biomarker utility of circulating miRs in patients with a diagnosis of osteoporosis and sarcopenia versus healthy controls and evaluated the shared miRs between these two pathological conditions. Th results of this review show that more than 69 circulating miRs were dysregulated and differentially expressed in osteoporosis, while only 14 miRs were dysregulated in sarcopenia. The small number of studies on sarcopenia is probably due to the variety of operational definitions used for diagnosis. Even in the studies included in this review, the diagnosis of sarcopenia was not clear, with sarcopenic parameters measured but not used to form a definite diagnosis. However, despite this, our review founded a moderate degree of overlap of dysregulated miRs between osteoporosis and sarcopenia, and this was probably due to the common factors shared between the pathological conditions, e.g., DNA damage, stem-cell depletion, and oxidative stress [8].
Ultimately, we identified nine shared miRs that are differentially expressed both in sarcopenia and osteoporosis. These findings are particularly novel, as miRs have not yet been explored in the context of osteosarcopenia syndrome. In this review, it was shown that the shared miRs between osteoporosis and sarcopenia were miR-23a-3p, miR-29a, miR-93, miR-133a, miR-155, miR-206, miR-208, miR-222, and miR-328. However, most of these shared miRs do not exhibit the same direction of dysregulation in osteoporosis and sarcopenia. Only miR-155, miR-206, and miR-328 showed the same dysregulation (downregulation) in both osteoporosis and sarcopenia. Furthermore, for most of the shared miRs found in this review, there has been no replication by more than one study, particularly for miRs analyzed in sarcopenic patients, while for osteoporosis, three shared miRs, i.e., miR-222, miR-23a, and miR-133a, were found in multiple studies.
MiR-133a is one of the most studied and best characterized miRs [85,86]. Specifically expressed in muscles, it has been categorized as myomiRs and is essential for appropriate skeletal muscle development and function. In addition to its role in muscle, various studies highlighted that miR-133a can also increase osteoclastogenesis due to mRNA targeting of the proteins that inhibit osteoclastogenesis [85]. In fact, it targets the RUNX2 gene 3 -UTR, a transcription factor indicated as a master regulator in the commitment to the osteoblastic cell line: when this miRNA is overexpressed, it showed a suppression of alkaline phosphatase (ALP) (a marker of osteoblast formation) production and, therefore, osteoblast differentiation [86]. Other muscle-specific miRs are represented by miR-206, miR-208, and miR-222, this last miR being critical for the process of myogenesis and homoeostasis of skeletal muscle [87][88][89][90]. Although miR-222 is clearly important for muscle cell development, the mechanisms by which it regulates myogenesis are still poorly defined. This is in part because the complete set of this miR targets is not known. Despite its roles in muscle, several studies suggested that miR-222 also plays a significant role in vascular formation, which is an essential part of fracture healing [91]. In this context, another miR associated with osteoporotic fracture is the miR-23a-3p, which is associated with osteogenic differentiation and is downregulated in patients with osteoporotic fractures [92]. Moreover, this miR also plays important roles in the myogenesis of skeletal muscle, fiber type determination, and exercise adaptation. In fact, it was shown that the overexpression of miR-23-3p could suppress muscle atrophy both in vitro and in vivo [93].
For some of the shared miRs in this review, there were limited studies in the context of both osteoporosis and sarcopenia, and therefore, their relevance is even less clear at present. From this perspective, even if miR-93 represents the most significantly downregulated miR during osteoblast mineralization [94], only one study on its expression was found for osteoporosis as well as for sarcopenia. Similarly, miR-29, which is implicated in mammalian osteoblast differentiation targeting extracellular matrix molecules and modulating Wnt signaling and regulators of fibrogenesis in muscle targeting ECM proteins such as collagens, fibrillins, and elastin [95][96][97][98][99][100][101], was studied in only one study for both osteoporosis and sarcopenia. Another shared miR between osteoporosis and sarcopenia is represented by miR-155. Wu et al. showed that suppressing the expression and function of this miR contributes to mitigating the inhibition of tumor necrosis factor (TNF)-α on bone morphogenetic protein (BMP)-2-induced osteogenic differentiation [95], indicating that there was a link between miR-155 and BMP signaling. Furthermore, this study also demonstrated that miR-155 facilitates skeletal muscle regeneration by balancing pro-and anti-inflammatory macrophages [102].
While this review followed the Cochrane approach in conducting a systematic review and used an authenticated tool for risk of bias (QUADAS2), achieving excellent inter-rater agreement and conducting screening and risk of bias assessments using more than one reviewer, several limitations must be considered. First, the heterogeneity of the studies identified in this review must be recognized. It is well-known that age affects miRs profiles; thus, older osteoporotic patients could have different miR profiles than younger postmenopausal osteoporotic patients. Similarly, men and women may display differing profiles within the same condition. Second, in several of the included studies, a poor selection of controls within and improper choice of diagnostic criteria, especially for sarcopenia, were present. Third, details about selection procedures and participant demographics were in some cases vague, sample sizes were small, and technical aspects of quality assurance were sometimes omitted.

Conclusions
This is the first review to examine the potential role of miRs in the context of osteosarcopenia syndrome, thus offering a new perspective on this topic. Here, we provided a complete overview of this topic and identified a panel of miRs that may be involved in osteosarcopenia. Considering the synergistic effect of osteoporosis and sarcopenia on the risk of adverse health outcomes (falls, hospitalization, worsening disability, and all-cause mortality), understanding the pathogenesis of osteosarcopenia syndrome has the potential to lead to effective screening, monitoring, or treatment strategies. However, this systematic review was primarily exploratory, and further research is required to validate the presented findings.