Short-chain fatty acids (SCFAs) are produced in the gut through the fermentation of dietary fiber by beneficial bacteria such as Bifidobacterium, Lactobacillus, and Lactococcus. These SCFAs enhance bone metabolism, increase bone mineral density, and facilitate calcium absorption (Ding et al., 2020; Li et al., 2020). Furthermore, gut-derived metabolites can influence bone metabolism through endocrine pathways by modulating hormones such as leptin, glucagon-like peptide-1 (GLP-1), and casein-derived peptides (Ding et al., 2020; José et al., 2025; Karsenty and Khosla, 2022; Liu H. et al., 2024; Schiellerup et al., 2019). They also regulate bone metabolism by modulating osteoblast (OB) and osteoclast (OC) activities through immune-mediated mechanisms.

Vitamin K synthesized by GM enhances bone mineralization by promoting osteocalcin carboxylation, whereas deficiencies in B vitamins have been strongly associated with reduced bone density (Ding et al., 2020; Li et al., 2020). Moreover, fermentation of dietary fiber by gut bacteria—including Bifidobacterium, Lactobacillus, and Lactococcus—produces SCFAs that are tightly linked to bone metabolism. Animal experiments have demonstrated that SCFAs supplementation significantly increases bone mass in mice, whereas antibiotic-induced SCFAs depletion leads to bone loss. SCFAs such as butyrate and propionate, regulate bone metabolism through two complementary mechanisms: directly enhancing bone density by inhibiting OC differentiation and stimulating OB activity, and indirectly promoting calcium absorption by lowering intestinal pH. Germ-free mouse models exhibit a marked reduction in osteoclast numbers, with bone metabolism restored after transplantation of normal microbiota, confirming that GM maintains bone homeostasis by balancing Th17 and Treg cells. Microbial dysbiosis can lead to excessive Th17 cell proliferation, producing pro-inflammatory cytokines such as IL-17 that activate OCs, whereas Treg cells secrete anti-inflammatory factors such as IL-10 and TGF-β, which inhibit bone resorption (Ding et al., 2020; Karsenty and Khosla, 2022; Liu H. et al., 2024). The gut hormone network plays a multidirectional role in bone metabolism. Gastric inhibitory polypeptide (GIP) promotes bone formation by activating osteoblast receptors, with genetic polymorphisms in its receptor being linked to decreased bone density in humans. GLP-1 regulates bone metabolism bidirectionally via the cAMP/PKA signaling pathway, promoting osteogenic differentiation while inhibiting OC activity. Its receptor agonist, liraglutide, has shown beneficial effects on bone microarchitecture in OP models. Meanwhile, GLP-2 indirectly suppresses bone resorption by modulating parathyroid hormone (PTH) or calcium absorption, whereas peptide YY (PYY) acts via the Y1 receptor to inhibit osteogenesis and enhance bone resorption. Clinical studies indicate that low PYY levels in obese individuals are associated with high bone density, whereas elevated PYY levels following bariatric surgery lead to bone loss (José et al., 2025; Karsenty and Khosla, 2022; Liu H. et al., 2024; Schiellerup et al., 2019).

Overall, GM can enhance bone strength through the synthesis of essential nutrients. Additionally, it can influence bone metabolism either directly via metabolic byproducts or indirectly through immune and hormonal pathways, thereby regulating OB and OC functions.

The activity, diversity, and metabolic products of the GM are closely associated with muscle mass and function (Li W. et al., 2024; Ticinesi et al., 2019b).

In recent years, numerous studies have demonstrated a strong biomechanical and molecular biological link between bone and skeletal muscle. Bone tissue can sense both external and internal mechanical stresses and transduce mechanical loads into biological signals (Benjamin et al., 2006; Regan et al., 2017b; Schoenau, 2005; Watanabe-Takano et al., 2021; Yin et al., 2024). During physical activity, muscle contraction generates mechanical forces that stimulate bone cells, activating the osteocyte lacuno-canalicular system, thus promoting bone growth (Bergmann et al., 2010; McCrory et al., 2013; Shiba et al., 2015; Vickerton et al., 2014; Zhao et al., 2023). Additionally, skeletal muscle secretes myokines, which enhance OB activity, promote bone tissue metabolism, and help maintain normal bone mineral density (Juffer et al., 2014). Furthermore, bone-derived factors—including osteocalcin, fibroblast growth factor-23 (FGF-23), sclerostin, and prostaglandin E2 (PGE2)—that influence the proliferation and differentiation of myogenic cells, enhance muscle mass, and maintain normal muscle size and strength (Huang et al., 2017; Liu et al., 2017; Mera et al., 2017a; Mera et al., 2017b).

Overall, the relationship between muscles and bone is indirectly maintained through mechanisms such as biomechanics and the secretion of cytokines, which influence the normal growth and metabolism of both muscles and bones (Li et al., 2019).

In summary, accumulating evidence suggests that the GM is an important regulatory component of the ‘gut–muscle–bone axis’, interacting bidirectionally with muscle and bone. The dynamic bidirectional communication between muscle and bone further amplifies the impact of GM on the musculoskeletal system. This crosstalk involves biomechanical interactions as well as endocrine and paracrine signaling pathways, in which muscle-derived myokines such as IGF-2 and irisin promote osteogenesis, while bone-derived factors such as osteocalcin and sclerostin regulate muscle metabolism and strength (Mao et al., 2024; Sui et al., 2024). Therefore, the mutual regulation between muscle and bone forms a complex feedback network that integrates mechanical, hormonal, and metabolic cues, thereby reinforcing the systemic influence of GM on both tissues. The detailed mechanisms underlying this bidirectional regulation are discussed in Section 2.3.

Metabolic products of the GM are closely associated with both muscle and bone. For example, a study by Ríos-Covián et al. (2016) reported that SCFAs—primarily acetate, propionate, and butyrate—are generated by fermenting dietary fibers with gut bacteria such as Bifidobacterium, Lactobacillus, and Prevotella species. These SCFAs exert broad systemic regulatory effects. SCFAs enhance intestinal absorption of calcium and magnesium in the gut, thereby stimulating OB activity and increasing bone mineral density (Lucas et al., 2018). Additionally, SCFAs improve insulin sensitivity, enhance muscle glucose uptake (Huang and Czech, 2007), and promote mitochondrial function by activating the AMPK signaling system, which increases muscle metabolism and function (Frampton et al., 2020).

Both muscle and bone are adversely affected by systemic inflammation originating from the gut. Research indicates that gut barrier integrity is compromised in chronic inflammatory conditions such as obesity, metabolic syndrome, age-related inflammation, and acute inflammatory responses. Lipopolysaccharides (LPS), a bacterial byproduct, can also enter the bloodstream and cause systemic inflammation, which harms the musculoskeletal system (Ke et al., 2019). Pro-inflammatory cytokines, including TNF-α and IL-6, stimulate OC differentiation and activity, thereby enhancing bone resorption (Nardone et al., 2021). These inflammatory mediators also promote muscle protein degradation and inhibit protein synthesis, resulting in muscle atrophy and reduced strength. Therefore, systemic inflammation linked to GM dysbiosis may simultaneously impair bone and muscle, a phenomenon commonly observed in elderly individuals and patients with chronic diseases.

The musculoskeletal system is also linked to endocrine regulation within the gut system. Research confirms that several hormones—such as GLP-1, GIP, and leptin—are secreted by gut cells (Baggio and Drucker, 2007). These hormones influence metabolic processes and regulate both bone and muscle through endocrine pathways. GLP-1 and GIP can regulate the activity of OB and OC, promoting bone metabolism balance. Furthermore, leptin demonstrates multifaceted roles in regulating musculoskeletal metabolism. Recent research reveals that leptin enhances local energy expenditure within skeletal muscle. This is achieved through the upregulation of type 2 deiodinase (D2), which boosts the intramuscular conversion of thyroxine (T4) to active triiodothyronine (T3), thereby elevating the basal metabolic rate (Miro et al., 2025). This anabolic energy environment is postulated to be conducive to protein synthesis and tissue repair. Thus, gut-derived hormones regulate systemic energy homeostasis, exerting coordinated effects on both bone and muscle metabolism.

The gut–muscle–bone axis is an integrative framework describing interactions among the GM, skeletal muscle, and bone. Within this axis, the GM is increasingly recognized as an important regulatory node that may influence musculoskeletal homeostasis through metabolic, immune, and endocrine pathways. Importantly, regulation is bidirectional: muscle- and bone-derived signals can, in turn, shape gut microbial composition and function. Accordingly, the GM is best viewed as an integral component of a dynamic, multi-organ regulatory network rather than a unidirectional driver. Through metabolite-mediated, immune, and endocrine mechanisms, the GM may modulate both muscle and bone function. Meanwhile, muscle and bone communicate bidirectionally via mechanical loading and the secretion of myokines and osteokines (e.g., osteocalcin), which coordinately contribute to maintaining musculoskeletal homeostasis.

Moreover, the status of muscle and bone can influence the GM indirectly. Following GM modulation, secreted factors from muscle and bone can alter systemic metabolism and provoke inflammatory responses, which in turn may impact GM composition. Thus, the GM, muscle, and bone form a closed-loop feedback system that maintains the balance of the musculoskeletal system and metabolic functions as a whole.

Accordingly, this article connects these three factors and constructs the “gut-muscle-bone Axis,” as illustrated in Figure 1.

Figure 1 delineates the integral role of the GM in regulating bone and muscle homeostasis, illustrating the pathways through which its disruption may contribute to OS-related changes. The interactions are color-coded.

Vitamin pathways (Red): Gut microbiota-derived vitamins, particularly vitamin K, promote bone mineralization through osteocalcin carboxylation, while B vitamin deficiencies are linked to reduced bone density.

SCFA pathways (Yellow): SCFAS, produced by microbial fermentation of dietary fiber, enhance bone mineral density and calcium absorption, and directly regulate osteoblast and osteoclast activity. Simultaneously, SCFAs activate the AMPK signaling pathway to modulate systemic energy metabolism, improve insulin sensitivity, and help preserve muscle mass and function.

Intestinal hormone pathways (Blue): Gut-derived hormones such as GLP-1 and leptin influence bone metabolism through endocrine signaling and contribute to maintaining muscle metabolic homeostasis.

Additionally, muscle and bone engage in direct crosstalk via mechanical coupling and biochemical dialog, further integrating these three physiological systems.

Integrity of the intestinal barrier is essential for maintaining systemic health. The GM preserves this integrity by regulating tight junction proteins in epithelial cells, including occludin, claudin-1, and zonulin. Dysbiosis reduces the expression of these proteins, increasing intestinal permeability. This increased permeability allows endotoxins such as lipopolysaccharide (LPS) to translocate into the bloodstream, triggering systemic inflammation via elevated inflammatory cytokines (e.g., TNF-α, IL-6, IL-17) and activating osteoclastogenesis through the RANKL/OPG pathway, thereby triggering systemic inflammation that adversely affects bone and muscle health (Di Vincenzo et al., 2024; Guan et al., 2023). Simultaneously, microbial-derived SCFAs such as acetate, propionate and butyrate—which normally support epithelial barrier integrity and anti-inflammatory signaling—are reduced in dysbiosis, further increasing barrier damage and promoting muscle catabolism through oxidative stress and elevated myokine release (e.g., myostatin) and increased creatinine/cystatin C (Cr/CysC) levels as markers of muscle degradation (Han et al., 2022; Lustgarten, 2019).

Moreover, the disrupted barrier allows dissemination of bacterial metabolites and inflammatory mediators into the circulation, which can impair bone–muscle crosstalk: for instance, altered levels of osteokines (e.g., osteocalcin, sclerostin, FGF-23, PGE2) released from bone may modify muscle regeneration and vice versa, thus linking intestinal barrier dysfunction with the downstream dysregulation of the gut-muscle-bone Axis (Chu et al., 2025; Wang Y. et al., 2023). Together, these mechanisms—increased LPS-driven endotoxaemia, decreased SCFA-mediated protection, elevated inflammatory cytokines, disturbance in Cr/CysC as muscle/bone degradation markers, and altered osteokine signaling—form a pathological cascade initiated by intestinal mucosal barrier disruption which ultimately influences both bone and muscle mass and function.

The GM dysbiosis perturbs immune homeostasis by modulating the balance between T-helper 17 (Th17) cells and regulatory T cells (Tregs). Specifically, GM imbalance decreases Treg counts and enhances Th17 cell differentiation. The increased Th17 cell population secretes interleukin-17 (IL-17), which promotes OC differentiation and bone resorption, primarily by activating the Receptor Activator of Nuclear Factor kappa-B Ligand (RANKL) pathway. Concurrently, the reduction in Tregs diminishes their secretion of anti-inflammatory factors such as IL-10 and TGF-β, thereby weakening their inherent inhibitory effect on osteoclastogenesis. This collective dysregulation—enhanced pro-osteoclastic signaling via Th17/IL-17 and diminished anti-osteoclastic suppression from Tregs—synergistically exacerbates bone loss (Raphael et al., 2015).

By promoting B cell proliferation, GM dysbiosis raises the RANKL/osteoprotegerin (OPG) ratio and speeds up the creation of OC. On the other hand, GM dysbiosis inhibits Wnt/β-catenin signaling, which lowers OB production of OPG and speeds up bone loss, ultimately leading to OP (Chen et al., 2021).

Studies indicate that a decline in anti-inflammatory bacteria and an increase in pro-inflammatory bacteria contribute to chronic inflammation, markedly impairing muscle mass and function (Farini et al., 2023; Nardone et al., 2021). Inflammatory cytokines have been reported to inhibit insulin-like growth factor 1 (IGF-1) synthesis, thereby decreasing its levels in muscle tissue. In the case of GM dysbiosis, the secretion of pro-inflammatory factors such as IL-6 and TNF-α increases, and these factors inhibit the synthesis of IGF-1, accelerating protein catabolism. These changes suppress muscle protein synthesis, impair muscle metabolism, and ultimately contribute to SP (Yoo et al., 2018).

The GM imbalance disrupts hormone secretion and alters the synthesis of key metabolic products, thereby affecting bone and muscle function.

The GM influences bone and muscle metabolism both directly and indirectly by modulating nutrient and energy absorption.

The GM ferments prebiotic fibers into SCFAs, which modify the gut environment and subsequently impact bone health. SCFAs facilitate calcium absorption by reducing intestinal pH and forming mineral complexes (e.g., calcium phosphate), thereby promoting bone growth and maintenance (Whisner et al., 2016). Vitamin D absorption is closely related to bone health. Research has shown that the composition of the GM has a significant impact on vitamin D absorption. Higher Prevotella abundance in the GM is associated with enhanced vitamin D absorption, whereas increased Bifidobacterium levels correlate negatively with 25-hydroxyvitamin D concentrations (Boughanem et al., 2023). These findings suggest that specific GM compositions can indirectly influence bone health by modulating vitamin D absorption.

In addition, dietary carbohydrate metabolism is influenced by GM: undigested carbohydrates reach the colon where microbes ferment them, producing SCFAs and other metabolites which feed into host energy metabolism and lipid synthesis pathways. Altered GM composition can shift carbohydrate to SCFA conversion and thereby modulate host glycaemic control, insulin sensitivity and substrate availability for muscle anabolism and bone remodeling (Perler et al., 2023).

In terms of lipid metabolism, the GM modulates bile acid metabolism through bile salt hydrolase activity, thereby influencing lipid digestion and absorption, as well as the bioavailability of fat-soluble vitamins such as vitamin D. Secondary bile acids function as signaling molecules that activate FXR and TGR5 receptors, participating in the regulation of systemic energy homeostasis and inflammatory responses. Dysbiosis may lead to the translocation of endotoxins like LPS, which activates macrophages via the TLR4 pathway, prompting the production of pro-inflammatory cytokines such as TNF-α. This, in turn, promotes muscle protein breakdown and bone resorption (Brown et al., 2023).

The GM also plays an important role in regulating protein metabolism. Both dietary and endogenous proteins are hydrolyzed into amino acids and peptides by host and bacterial proteases and peptidases. The resulting amino acids are utilized by host cells and also support microbial growth (Ticinesi et al., 2019a). Gut symbiotic bacteria are crucial for the degradation, synthesis, and absorption of amino acids, especially in the metabolism of key amino acids such as alanine, aspartic acid, glutamic acid, glycine, and tryptophan (Grenier et al., 2023; Oh et al., 2021). Compared with specific pathogen–free mice, germ-free mice show distinct alterations in amino acid distribution throughout the gastrointestinal tract, indicating that the GM is critical for maintaining amino acid balance and host metabolic health (Sasabe et al., 2016). Additionally, the GM can use inorganic nitrogen (such as ammonium salts) to synthesize essential amino acids, and some bacterial strains can even use elemental nitrogen to synthesize organic nitrogen (Cosio and Powers, 2023). The GM is also capable of synthesizing amino acids such as tryptophan, a key substrate for skeletal muscle protein synthesis and metabolism (Jiang et al., 2022). Tryptophan activates the IGF1/p70S6K/mTOR signaling pathway, upregulating genes involved in myofibril synthesis and promoting skeletal muscle growth and function (Dukes et al., 2015).

The GM not only participates in amino acid synthesis but also plays a key role in the synthesis of vitamins. A healthy GM, particularly Bifidobacterium and Lactobacillus, synthesizes various B vitamins and vitamin K, essential for bone and muscle health (Li et al., 2016; Wong et al., 2018). Compounds produced or modified by the GM, such as folate, vitamin B12, and tryptophan, can enter the systemic circulation and subsequently influence bone and muscle metabolic functions. SCFAs, metabolic products of GM, have been shown to enhance muscle cell growth and development, thereby increasing muscle mass. For instance, propionate—a major SCFA—stimulates glucose uptake in C2C12 myotubes and promotes muscle growth (Han et al., 2014). Thus, SCFAs support normal muscle metabolism and quality.

Muscle-bone interactions are crucial in the pathogenesis of OS. Disruption of this balance triggers crosstalk, leading to OP and muscle atrophy, which further accelerates OS progression.

Diet is fundamental for regulating the GM, maintaining bone health, and preserving muscle function (Devignes et al., 2022; Selvaraj et al., 2024; Zhang et al., 2023). High-protein diets (1.2–1.5 g/kg/day) enhance muscle mass and strength, which may delay SP onset and progression based on current evidence (Motiani et al., 2020). Protein sources significantly influence GM composition. Plant-based proteins tend to promote beneficial bacteria such as Bifidobacterium and Lactobacillus, whereas excessive animal protein intake is associated with increases potentially pathogenic taxa, including Bacteroides, Alistipes, Bilophila, and Clostridium perfringens (Cotillard et al., 2013; David et al., 2014; Prokopidis et al., 2020; Tomova et al., 2019). Compared to animal proteins, soy protein more effectively promotes Bacteroidetes and reduces serum LPS levels (Butteiger et al., 2016; Reichardt et al., 2014). Furthermore, certain plant-derived Lactobacillus and Bifidobacterium strains have been associated with increased muscle strength in rodents (Chen et al., 2016; Sprong et al., 2010). Excessive protein intake, especially from animal sources, may negatively affect bone health and should be moderated (Hao et al., 2024). Therefore, based on evidence primarily from studies on SP and OP, it is plausible that high-protein diets prioritizing plant-based sources may help counteract OS. However, direct intervention trials in OS cohorts are needed to confirm this synergistic benefit.

Notably, dietary fiber is another key factor. High dietary fiber consumption produces SCFAs, which enhance mucus secretion, increase antimicrobial peptide levels, and improve intestinal barrier function. In contrast, diets high in animal protein and low in fiber produce toxic metabolites, such as branched-chain fatty acids (BCFAs), leading to mucus degradation, reduced antimicrobial peptide levels, and impaired gut barrier function (Makki et al., 2018). Evidence indicates that high-fiber diets can attenuate the adverse effects of metabolic disorders on muscle mass by increasing GM diversity and circulating free fatty acid concentrations (Hevia-Larraín et al., 2021). Similarly, the European OP guidelines emphasize that physical inactivity and diets low in fiber but high in sugar and saturated fat are associated with promote chronic low-grade inflammation and obesity, thereby exacerbating OP (Biver et al., 2019). Given that chronic inflammation and metabolic dysfunction are also implicated in OS pathogenesis, these dietary factors are likely relevant to OS, though direct evidence is limited.

In summary, current evidence primarily from OP and SP research suggests the potential benefits of a diet high in plant protein, high in fiber, low in sugar, and low in saturated fat may be beneficial for the prevention and management of OS, The proposed mechanisms likely involve GM modulation, reduced inflammation, and improved nutrient absorption. However, dedicated dietary intervention studies in OS populations are warranted to establish specific nutritional guidelines. Dietary interventions represent a promising approach for OS management. Future research should focus on the nutritional status of OS individuals and the OS-specific regulatory role of GM in mediating dietary effects on bone and muscle health within the specific context of OS.

Probiotics and prebiotics have been reported to potentially contribute to protein synthesis and bone metabolism, effectively promoting muscle mass and bone mineral density (Kang et al., 2024; Schepper et al., 2017; Zhang et al., 2024). Probiotics, particularly Bifidobacterium and Lactobacillus, are considered essential for maintaining gut homeostasis For instance, Bifidobacterium supplementation modulates Gram-negative bacterial populations, maintaining homeostatic levels and reducing toxin absorption (de Marco et al., 2021). Supplementation with Lactobacillus improves protein and calcium absorption, decreases intestinal pH, and enhances peristalsis and nutrient uptake (Taslim et al., 2023). However, most of these findings derive from studies not specifically designed for OS, and their direct applicability to OS patients remains to be established.

Prebiotics are indigestible dietary fibers that selectively promote the growth and activity of beneficial gut bacteria (Davani-Davari et al., 2019). Prebiotic intake improves gastrointestinal function and muscle mass by modulating SCFAs. A previous clinical study showed that prebiotic supplements composed of inulin and fructooligosaccharides positively impacted healthy microbiota while enhancing hand strength and endurance in SP patients (Daily and Park, 2022). Fermentation of prebiotic fibers by the GM produces SCFAs and other metabolites that exert bone-protective effects. Dietary prebiotics, such as inulin, fructooligosaccharides, and resistant starch, enhance GM diversity and function, thereby reducing bone loss and improving bone health (Hao et al., 2024; Schepper et al., 2017).

Overall, probiotics and prebiotics show preliminary promise as preventive and therapeutic approaches for OS, though this is largely extrapolated from SP and OP research. However, their efficacy and safety in OS populations remain underexplored. Larger-scale, randomized controlled trials specifically designed for OS are needed to validate these interventions and determine optimal strains, doses, and treatment durations.

Substantial evidence indicates that both resistance training and endurance training effectively mitigate the progression of OP and SP. The benefits of exercise on bone and muscle are understood to extend beyond direct mechanical stimulation to include systemic modulation through the GM. Exercise acts as a potent modulator of the gut ecosystem (Hawley et al., 2025). Clinical studies have confirmed that exercise significantly reduces the Firmicutes/Bacteroidetes ratio, increases the abundance of SCFA-producing bacteria (e.g., Bacteroidetes), and enhances overall microbial diversity, thereby potentially promoting SCFA synthesis (Hu et al., 2020; Moreno-Pérez et al., 2018; Sales and Reimer, 2023).

Within the “gut-muscle-bone Axis,” exercise-induced SCFAs—primarily butyrate, propionate, and acetate—are proposed to serve as crucial signaling molecules. In bone metabolism, SCFAs facilitate calcium absorption and bone mineralization by lowering intestinal pH and forming soluble calcium complexes, while concurrently inhibiting osteoclast differentiation and promoting osteoblast activity (Lucas et al., 2018; Ríos-Covián et al., 2016). In skeletal muscle, SCFAs improve insulin sensitivity, activate the AMPK signaling pathway, promote mitochondrial biogenesis, and upregulate the expression of neuromuscular junction proteins, thereby enhancing protein synthesis and reducing degradation (Carey and Montag, 2021; Qi et al., 2021; Walsh et al., 2015).

Furthermore, studies suggest that resistance training can enhance intestinal barrier integrity by reducing zonulin levels and promoting mucin production, thereby decreasing endotoxin translocation and intestinal inflammation, which in turn helps protect the musculoskeletal system from systemic inflammatory damage (Wagner et al., 2024). The exercise-induced increase in beneficial bacteria such as Bacteroidetes also contributes to mitigating the adverse effects of inflammatory mediators like TNF-α and IL-6 (Hu et al., 2020; Varghese et al., 2024).

In summary, while exercise is a well-established intervention for OP and SP, and its benefits are hypothesized to extend to OS through GM-mediated mechanisms. The development of standardized exercise guidelines—regarding timing, intensity, and modalities—tailored to OS patients represents a critical direction for future research and clinical translation.

Antibiotic exposure is widely recognized as a factor that alters GM composition and function, and excessive or inappropriate use can produce deleterious consequences for musculoskeletal health. Broad-spectrum antibiotics, especially when used repeatedly, disrupt microbial diversity, reduce populations of short-chain-fat-acid-producing bacteria, and shift the microbial balance toward taxa associated with inflammation and dysmetabolism. For example, animal studies indicate that in mice treated with high-dose broad-spectrum antibiotics, bone mineral density (BMD) was reduced, osteoblastogenesis inhibited and osteoclast activity increased, relative to untreated controls (Zhao et al., 2021). Likewise, antibiotic treatment in piglets has been shown to altered GM composition and gene expression related to muscle fiber type and lipid metabolism in skeletal muscle, suggesting a link from antibiotics, GM perturbation, muscle quality degradation (Yan et al., 2020). These findings derive from animal studies and have not yet been validated in human OS populations.

Given that both bone and muscle depend on a healthy gut-microbiome ecosystem for optimal nutrient absorption, metabolite production, immune regulation, and endocrine signaling, antibiotic-induced microbial dysbiosis may accelerate the progression of OS by undermining these pathways. However, direct evidence linking antibiotic use to OS onset or progression in humans remains limited and largely inferential.

Therefore, while current understanding supports the rational and judicious use of antibiotics in clinical practice, along with the consideration of microbiota-restorative strategies (e.g., probiotics, dietary fiber, and prebiotics) following treatment, it should be acknowledged tha these recommendations are extrapolated from broader musculoskeletal and microbiological research rather than from OS-specific studies. Further observational and interventional research in at-risk and OS-diagnosed human cohorts is needed to clarify the role of antibiotics in OS pathogenesis and to develop evidence-based antimicrobial stewardship guidelines for this population.

Recent studies indicate that FMT can regulate and restore GM and its associated metabolites, thereby improving SP-related malnutrition, muscle loss, and overall health, including bone metabolism (Biazzo and Deidda, 2022; Kim et al., 2022; Zhang T. et al., 2022; Zhang Y. W. et al., 2022). FMT can enhance GM and its metabolites, promoting skeletal muscle mass recovery, improving muscle function, and mitigating or preventing SP (Xiao et al., 2024). Fielding et al. (2019) demonstrated that germ-free mice receiving fecal bacteria from elderly individuals with better physical function exhibited significantly greater muscle strength than those receiving bacteria from frail older adults.

Additionally, a review suggested that SCFAs, after FMT, may regulate bone metabolism through multiple mechanisms, including reducing inflammation, enhancing intestinal calcium absorption, promoting osteoblast differentiation via Tregs, and directly inhibiting osteoclast differentiation (Zhang Y. W. et al., 2022). Yan et al. (2016) highlighted that SCFAs indirectly preserve bone mass by modulating serum IGF-1 levels. Thus, FMT may increase SCFA levels, regulate bone metabolism via multiple pathways, maintain bone formation-resorption balance, and help prevent OP.

In conclusion, while FMT represents a promising exploratory approach for modulating both bone and skeletal muscle function based on extrapolation from SP and OP studies, it must be emphasized that its efficacy and safety as a clinical strategy for OS mitigation or prevention remain largely unproven. Future research should prioritize well-designed, OS-specific preclinical models and early-phase clinical trials to evaluate the therapeutic potential, optimal protocols, and long-term outcomes of FMT in this population.

Based on the evidence summarized above, we systematically present in Table 1, the primary intervention strategies for modulating the GM to potentially alleviate OS. It should be noted that most current evidence derives from studies on OP or SP individually; direct evidence from OS-specific intervention trials remains limited. Therefore, the strategies listed are largely extrapolated from related musculoskeletal conditions and warrant further validation in targeted OS cohorts.

Table 1 summarizes intervention strategies potentially relevant to OS-related outcomes through GM modulation. The table concisely integrates information on the types of interventions, their respective study designs, evidence level/source, observed changes in GM composition, resultant effects on bone and muscle endpoints, and potential limitations. This structured overview highlights the current inferential nature of the evidence base for targeting the “gut-muscle-bone Axis” and underscores the urgent need for direct, OS-focused research to develop effective management strategies.

SP and OP are both strongly associated with advancing age, with their prevalence showing a significant upward trend worldwide. Osteoporosis was operationally defined by the World Health Organization(WHO) in 1994 as a bone mineral density 2.5 standard deviations or more below the young adult mean, a criterion that remains the global diagnostic reference standard. Meanwhile, Kanis (1994) has operationally defined osteoporosis, which is now widely integrated into clinical practice (Edwards et al., 2015). In contrast, sarcopenia was only formally recognized as a distinct disease entity in the International Classification of Diseases in 2016, and its diagnostic criteria have not yet been fully standardized globally, posing challenges for accurately assessing its disease burden (Gielen et al., 2023). SP is currently defined according to the revised European Working Group on Sarcopenia in Older People (EWGSOP2) consensus, which emphasizes low muscle strength as the primary diagnostic criterion, supported by low muscle quantity and impaired physical performance (Cruz-Jentoft et al., 2019). It should be noted that OS, which describes the co-occurrence of OP and SP, currently lacks a unified diagnostic definition issued by the WHO (Papaioannou and Kennedy, 2015; Sepúlveda-Loyola et al., 2020). Nevertheless, multiple studies confirm that the two conditions frequently coexist. One clinical study indicates that, depending on the diagnostic criteria used, the prevalence of SP ranges from 28.3 to 55.0%, and it is significantly associated with OP (Zhan et al., 2025). These patients face multiple challenges, including a significantly elevated fracture risk, severely impaired physical function, and a decline in quality of life (Cao et al., 2024). From a socioeconomic standpoint, these two diseases and their complications, such as fractures and disability, contribute to enormous direct medical costs and indirect caregiving expenses, placing continuously growing pressure on healthcare systems (Clynes et al., 2021). Meanwhile, evidence indicates that the significant association between OS and mortality risk cannot be overlooked (Westbury et al., 2024). Patients with OS face a further elevated mortality risk due to fractures, complications, and overall deterioration of health status (Yi et al., 2025).

Although the diagnostic framework for OS remains under development (Sepúlveda-Loyola et al., 2020), its health impact in older adults is increasingly recognized/appears substantial, although standardized diagnostic criteria and high-quality OS-specific clinical evidence remain limited. This syndrome not only substantially elevates individual health risks but also continuously strains public health systems through high medical and caregiving costs, underscoring the urgent need to establish standardized diagnostic criteria and implement targeted prevention and intervention strategies.

Despite the substantial clinical burden imposed by OS, elucidating its underlying pathophysiological mechanisms remains a significant scientific challenge. To investigate the complex nature of this syndrome, research utilizing animal models has become an indispensable preclinical tool. Such studies not only provide critical insights into the pathogenesis of OS but also establish essential platforms for evaluating potential therapeutic interventions. However, existing models primarily capture isolated aspects of OS rather than the full complexity of the condition.

Natural aging models can better reproduce age-related musculoskeletal degeneration, but the modeling cycle is too long (Liang et al., 2022), ovariectomy models are mainly suitable for studying estrogen deficiency-related musculoskeletal metabolic abnormalities and cannot simulate OS caused by other etiologies (Beranger et al., 2015); chemically induced models can rapidly establish OS models, but their drug toxicity may interfere with the accuracy of mechanistic studies (Williams-Dautovich et al., 2017); genetically modified models can target specific gene functions, but their single gene defects often fail to reflect the polygenic interactions seen in human OS (Mito et al., 2015).

Furthermore, there is insufficient research on the temporal dynamics of existing models. As a progressive disease, different stages of OS may involve different pathological mechanisms. However, most current models only reflect the pathological state at a single time point, lacking simulation of the entire disease process. Simultaneously, a gap exists between models and clinical reality: clinically, OS patients often have multiple comorbidities and drug treatments, whereas experimental animal models are often established in strictly controlled environments, making it difficult to fully simulate the actual clinical scenario. This highlights the ongoing need for model refinement and the cautious translation of preclinical findings.

An increasing body of evidence indicates that the gut microbiota (GM) is closely associated with musculoskeletal health and may be involved in the pathophysiology of disorders such as OP and SP (Chen et al., 2023; Li et al., 2021). Mechanistically, GM dysbiosis may compromise intestinal barrier integrity, facilitating the translocation of endotoxins like LPS and triggering chronic low-grade systemic inflammation. This inflammatory state has been linked to enhanced osteoclastogenesis via RANKL up-regulation in bone and may impair muscle protein synthesis via down-regulation of anabolic mediators like IGF-1 (Indrio and Salatto, 2025; Li T. et al., 2024). Concurrently, GM-derived metabolites, particularly SCFAs, have been shown to modulate endocrine signaling and enhance nutrient bioavailability, thereby supporting both bone formation and muscle maintenance (Hwang et al., 2025). This crosstalk is integrated within a dynamic network involving muscle and bone, mediated by myokines (e.g., irisin) and osteokines (e.g., osteocalcin, OCN), and mechanical stimuli from muscle contractions that promote bone remodeling (Li et al., 2021). The conceptual framework of the “gut–muscle–bone axis” proposed in this review integrates these interactions, thereby suggesting a potential association between dysregulation of this axis and the progression of OS.

Within this conceptual framework, several microbiota-oriented strategies have been explored for their potential relevance to OS. Dietary interventions enriched in high-quality protein (particularly plant-based) and dietary fiber may promote SCFA production and increase GM diversity, supporting bone and muscle health (Giron et al., 2022; Hughes and Holscher, 2021). Supplementation with probiotics and prebiotics represents a promising approach, with early data indicating benefits for nutrient absorption, inflammatory modulation, and SCFA production, thereby contributing to improved bone and muscle metabolism (Cooney et al., 2020; Giron et al., 2022). Exercise, particularly resistance training, not only directly benefits muscle and bone but also modulates GM composition, further supporting the axis (Li et al., 2021; Ticinesi et al., 2025). Although in early exploratory stages, fecal microbiota transplantation (FMT) represents a novel approach for restoring GM composition, with preliminary evidence suggesting potential to attenuate muscle loss and enhance bone metabolism, though its safety and efficacy in OS require further validation (Hwang et al., 2025; Li et al., 2021).

Despite these advancements, the current evidence base has notable limitations. Most evidence is still derived from studies focusing solely on OP or SP, with research specifically using OS as a predefined endpoint being relatively limited and scattered. Clinically, there is a scarcity of large-scale randomized controlled trials (RCTs) for OS interventions. Methodologically, assessment protocols for GM and dual musculoskeletal endpoints lack standardization. To overcome these challenges, future research must prioritize several key directions: (1) conducting large-scale, longitudinal RCTs with standardized OS diagnostic criteria and dual primary endpoints; (2) elucidating the precise molecular mechanisms by which GM-derived metabolites influence myocyte and osteocyte function; (3) developing more clinically relevant animal models of OS; and (4) exploring personalized intervention strategies based on individual GM profiles, genetics, and OS phenotypes (Li et al., 2025).

In conclusion, OS is a multifactorial condition arising from complex interactions among aging, metabolic regulation, inflammation, and musculoskeletal decline. This review highlights the gut–muscle–bone axis as an integrative framework that synthesizes current mechanistic and associative evidence. While modulation of the GM through dietary, probiotic/prebiotic, exercise, and potentially FMT-based approaches shows promise, these strategies should be regarded as exploratory rather than established therapies. Further OS-specific clinical and translational studies are required before definitive conclusions regarding causality or therapeutic efficacy can be drawn.