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Review Gut, bone, and muscle: the triad of osteosarcopenia in inflammatory bowel disease
Shilpa Sharma,orcid

DOI: https://doi.org/10.5217/ir.2024.00185
Published online: April 29, 2025

Department of Medicine–Western Health, Australian Institute for Musculoskeletal Science, The University of Melbourne, Melbourne, Australia

Correspondence to Shilpa Sharma, Department of Medicine-Western Health, Australian Institute for Musculoskeletal Science, The University of Melbourne, 176 Furlong Road, St. Albans, VIC 3021, Australia. E-mail: shilpa.sharma@unimelb.edu.au
• Received: November 9, 2024   • Revised: February 17, 2025   • Accepted: March 6, 2025

© 2025 Korean Association for the Study of Intestinal Diseases.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Inflammatory bowel disease (IBD) is a group of chronic inflammatory conditions affecting the gastrointestinal tract that can lead to multiple systemic complications. Among these, osteosarcopenia has emerged as a significant concern, characterized by the concurrent deterioration of bone density and muscle mass, strength, and function. This dual deterioration significantly elevates the risk of falls and fractures, thereby exacerbating morbidity and diminishing quality of life. The pathogenesis of IBD-associated osteosarcopenia is multifactorial, with chronic intestinal inflammation serving as a central driver. Pro-inflammatory cytokines simultaneously disrupt bone homeostasis and muscle metabolism, creating a catabolic environment that impacts both tissues. Nutritional deficiencies, common in IBD due to malabsorption and decreased dietary intake, further compromise both bone mineralization and muscle protein synthesis. Management requires a comprehensive approach combining nutritional optimization, structured physical therapy, and lifestyle modifications. Pharmacological interventions integrate disease-specific treatments with targeted therapies including vitamin D supplementation, hormonal treatments, and bisphosphonates when indicated. This review synthesizes current evidence regarding the prevalence, pathogenesis, and clinical impact of osteosarcopenia in IBD, highlighting areas requiring further investigation.
  • Keywords: Inflammatory bowel disease; Osteoporosis; Sarcopenia; Bone loss; Muscle loss
Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic immunemediated inflammatory condition characterized by periods of active disease and remission. Historically prevalent in Westernized countries, IBD incidence has been rising in the newly industrialized countries [1-3].
Beyond the gastrointestinal system, IBD manifests in multiple organs as extraintestinal manifestations [4]. The initial trigger occurs when disruption of the intestinal epithelial barrier allows gut microbial antigens to penetrate underlying tissues, leading to inflammatory cytokine release (including tumor necrosis factor [TNF]-α, interleukin [IL]-1β, IL-6) and establishing a systemic inflammatory cycle [5]. However, inflammation alone does not fully explain extraintestinal manifestations. Additional factors include genetic predisposition, environmental triggers shared with IBD, gut dysbiosis, and impaired nutrient absorption affecting organ function and hormone production [4,5].
The musculoskeletal system is particularly vulnerable to concurrent bone and muscle deterioration among these systemic manifestations. In IBD patients, musculoskeletal complications commonly present as osteosarcopenia, occurring independently of age. While osteoporosis manifests as reduced bone mineral density (BMD) and microstructural deterioration leading to increased fracture risk [6], sarcopenia involves progressive loss of skeletal muscle mass, strength, and function [7,8]. The definition and assessment of these conditions in IBD require special consideration, as muscle loss can range from simple reduction in mass to complex functional deficits, while bone loss often follows atypical patterns unlike the gradual progression through osteopenia to osteoporosis seen in age-related cases [9-11].
Multiple mechanisms mediate the intricate relationship between muscles and bones. These include myokines (insulin-like growth factor [IGF]-1, fibroblast growth factor-2, myostatin), osteokines (IGF-1, osteocalcin, sclerostin), endocrine factors (testosterone, estrogen), and genetic factors (e.g., peroxisome proliferator-activated receptor-gamma coactivator 1-alpha [PGC-1α]) [12]. Muscle-bone interactions are further influenced by mechanical loading, where muscle contractions during physical activity stimulate bone maintenance and strength.
IBD-associated osteosarcopenia presents unique challenges due to its accelerated onset, complex pathophysiology (Table 1) [7,13-32]. The distinct pathological pattern emerges from the interplay of pro-inflammatory cytokines, altered gut microbiota, nutritional deficiencies, and medication effects, particularly glucocorticoids (GCs), leading to accelerated musculoskeletal deterioration [33]. Traditional diagnostic criteria for age-related osteosarcopenia may inadequately capture IBD-specific characteristics, necessitating specialized assessment approaches for early identification and monitoring.
Management requires an integrated approach combining non-pharmacological interventions with targeted pharmacological therapy. Non-pharmacological strategies include nutritional optimization and exercise programs adapted to disease activity. Pharmacological options encompass biological agents (anti-TNF-α, anti-IL-6), bone-specific treatments (bisphosphonates, denosumab), and nutritional supplementation (vitamin D, calcium) to address both inflammatory and musculoskeletal manifestations [34,35]. Treatment selection requires careful consideration of disease activity, individual risk factors, and potential contraindications.
This review examines IBD-associated osteosarcopenia through an integrated lens, evaluating current diagnostic criteria, assessment tools, and evidence-based therapeutic strategies. Understanding these distinct aspects enables healthcare providers to implement targeted preventive and therapeutic measures, optimizing musculoskeletal health in this unique patient population.
The pathophysiology of osteosarcopenia in IBD represents a complex interplay of systemic inflammation, malnutrition, physical inactivity, and treatment-related effects. These factors create synergistic interactions that accelerate both bone and muscle deterioration (Fig. 1). The chronic nature of IBD, coupled with disease-related lifestyle modifications and cumulative treatment effects, presents unique challenges in identifying specific pathogenic mechanisms. This complexity is further enhanced by the bidirectional relationship between bone and muscle health, where deterioration in one tissue often negatively impacts the other.
1. Chronic Inflammation-Mediated Bone and Muscle Loss
IBD-related chronic inflammation creates a systemic environment that simultaneously affects both bone and muscle tissues through interconnected pathways. The inflammatory process begins in the gut, where Th17 and Th1 cells produce pro-inflammatory cytokines such as interferon-γ, IL-6, and TNF-α, which migrate from the inflamed gut and establish a systemic inflammatory environment [20,36]. These inflammatory mediators trigger parallel deterioration in both musculoskeletal tissues through multiple signaling cascades.
In bone tissue, the receptor activator of nuclear factor kappa-β ligand (RANKL)/RANK/osteoprotegerin (OPG) axis is the central mechanism of bone loss. Osteoblasts produce both RANKL and OPG [37]. Th17 cells express RANKL and TNF-α, which directly promote osteoclast differentiation while suppressing OPG production by osteoblasts [38]. Osteoclastogenesis is negatively regulated by multiple factors, including OPG and OPG acts as a decoy receptor for RANKL, intercepting it before it can bind to RANK and thereby inhibiting osteoclast formation (Fig. 2A). Another factor, leucine-rich repeat-containing G-protein coupled receptor 4 (LGR4) competes with RANK for RANKL binding, providing an additional mechanism to modulate osteoclastogenesis [39,40]. The inflammatory environment stimulates the production of chemokines MCP-1 (monocyte chemoattractant protein-1) and MIP-1α (macrophage inflammatory protein-1α) by osteoblasts and other cells in the bone marrow. These chemokines (MCP-1 and MIP-1α) attract osteoclast precursors, leading to increased bone resorption [41-44].
Simultaneously in muscle tissue, these same inflammatory cytokines activate multiple catabolic pathways (Fig. 2B). These cytokines simultaneously activate the activin/myostatin/transforming growth factor (TGF)-β pathway and suppress the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway, promoting muscle atrophy [45]. A key mechanism involves the downregulation of IGF-1, an essential muscle growth factor. The IGF-1 signaling axis, operating through the PI3K/AKT/mTOR pathway and interacting with the forkhead box O (FOXO) pathway, plays a crucial role in muscle maintenance [46,47]. Myostatin emerges as a central mediator of muscle loss through multiple mechanisms. It inhibits Akt phosphorylation, thereby suppressing muscle differentiation and growth [48,49], while simultaneously activating nuclear transcription factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways to increase protein breakdown and inhibit myogenesis [50]. Furthermore, myostatin initiates a downstream cascade involving SMAD2/3 phosphorylation and SMAD4 complex formation, which translocates to the nucleus [45]. This nuclear translocation leads to gene expression changes that inhibit myoblast function and induce E3 ubiquitin ligases (Atrogin1 and MurF1), key mediators of protein degradation [51-53].
This orchestrated molecular response contributes significantly to the development of sarcopenia. CD patients have myopathy exemplified by myocyte apoptosis, modifications of myosin, and muscle atrophy [54].
In IBD, the balance shifts towards increased availability and activity of RANKL [55]. The binding of RANKL to RANK triggers the activation of TNF receptor-associated factor (TRAF) proteins, particularly TRAF6. This activation leads to the stimulation of NF-κB and MAPK signaling pathways, resulting in increased expression of transcription factors such as c-Fos and NFATc1. NFATc1, transcription factor of osteoclastogenesis, induces the expression of osteoclast-specific genes, including tartrate-resistant acid phosphatase (TRAP), cathepsin K, and MMP9. RANK activation also induces calcium oscillations, which further activate NFATc1 through calcineurin. Immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptors, such as DAP12 and FcRγ, provide essential costimulatory signals. These adaptors activate Syk and PLCγ2, contributing to calcium signaling and NFATc1 activation [56]. Additionally, IL-23, released by macrophages and dendritic cells, indirectly promotes osteoclastogenesis through the RANK/RANKL pathway [38].
The body attempts to counter these deteriorative processes through various compensatory mechanisms. In bone, OPG levels show variable responses [57-59], possibly as a homeostatic response to counteract pre-existing osteopenia [58]. In muscle, elevated mTORC1/p70S6k levels suggest attempts to maintain protein synthesis [60]. This integrated inflammatory response results in a complex interplay between bone resorption and muscle degradation, characterizing the osteosarcopenic phenotype in IBD.
2. Malnutrition and Malabsorption
Malnutrition and malabsorption in IBD compound the inflammatory effects on musculoskeletal tissues. Malnutrition affects up to 70% of all IBD patients and 38% of those in remission [61]. While traditionally considered more prevalent in CD (65%–75%) than UC (18%–62%) due to small intestinal involvement [18], recent studies suggest similar malnutrition rates in both conditions [62].
Multiple factors contribute to nutritional compromise. Decreased appetite, food avoidance behaviors, and restrictive diets often lead to reduced food intake [63]. Simultaneously, inflammation increases metabolic demands while impairing nutrient absorption [18]. This malnutrition can alter gut microbiome composition, triggering additional inflammatory responses and creating a self-perpetuating cycle [63].
Medication-related effects further complicate the nutritional status. GCs, sulfasalazine (a folic acid antagonist), and cholestyramine (which impairs fat absorption) can worsen nutritional deficits and promote muscle protein breakdown [36,64-66]. Additionally, inflammatory cytokines like IL-6 inhibit albumin promoter activity, leading to hypoalbuminemia and altered iron metabolism, resulting in anemia [66].
The interplay between malnutrition and malabsorption creates a synergistic effect that exacerbates osteosarcopenia in IBD. Even when dietary intake increases, malabsorption hampers efficient nutrient uptake [18,67]. Both conditions can increase gut permeability, further perpetuating inflammation and contributing to bone and muscle loss.
Depletion of muscle mass occurs in both UC and CD patients, regardless of disease phase [67]. However, the relationship between dietary factors and muscle function in this population remains unclear [68]. In children, malnutrition particularly impacts both bone mass accrual and muscle development during critical growth phases [69].

1) Vitamin D Deficiency

Vitamin D deficiency (30% insufficiency, 23% deficiency) is highly prevalent among patients with IBD [70,71]. The causes of low vitamin D levels are multifactorial, stemming from both IBD-related factors—such as restricted food intake, malabsorption, and inflammation—and non-IBD-related factors, including smoking, insufficient physical activity, poor enzymatic activation, and inadequate sunlight exposure [72-74]. Low serum vitamin D levels have been linked to higher disease activity, particularly in CD [75-79]. However, some studies suggest that patients with UC are more likely to experience vitamin D deficiency compared to those with CD [60,71,76]. Other studies, however, reported similarly low vitamin D levels in both UC and CD patients [72,80,81]. One study specifically found no correlation between disease activity and vitamin D deficiency in UC patients. 79 Interestingly, 22% of newly diagnosed IBD patients have normal serum vitamin D levels [82].
Vitamin D deficiency can lead to decreased BMD, increased risk of osteopenia and osteoporosis [83,84]. Furthermore, vitamin D deficiency alters bone mineral metabolism by significantly impacting the parathyroid (PTH) axis, leading to secondary hyperparathyroidism in IBD patients, especially those with CD [85,86]. Low vitamin D levels can lead to atrophy of fast-twitch type II muscle fibers, leading to reduced muscle strength [87]. CD patients with higher vitamin D levels exhibit greater muscle torque, suggesting that vitamin D insufficiency contributes to reduced muscle strength in CD [88].
Vitamin D regulates the expression of various proteins and pathways essential for muscle function through genomic effects, mediated by the vitamin D receptor (VDR). Specifically, these include calcium pumps, calcium-binding proteins, cytoskeletal proteins, and phosphate metabolism in muscle cells [89]. VDR is believed to be a key mediator of myogenesis and muscle contractility [71]. Additionally, vitamin D exerts non-genomic effects on muscle cells through the generation of second messengers, protein kinases, and activation of intracellular signal pathways [89]. The role of vitamin D extends to regulating myogenic transcription factors, such as IGF-2 and follistatin, which are crucial for the differentiation, proliferation, and regeneration of muscle stem cells [89]. Mager et al. [90] revealed a significant association between vitamin D levels and muscle mass in children with newly diagnosed IBD, with younger CD patients having suboptimal vitamin D levels showing the highest frequency of sarcopenia.

2) Calcium Deficiency

Among IBD patients, calcium deficiency is both common and a modifiable risk factor for osteoporosis [91]. Also, calcium deficiency decreases muscle spasms [18]. Optimal calcium absorption relies on vitamin D-dependent calcium transporters in the intestine [89,92]. However, inflammation in the gastrointestinal tract significantly impair calcium absorption. Impaired absorption of calcium and vitamin D, despite sufficient intake, lead to negative calcium balance and increased bone resorption [93]. Nonetheless, CD-specific factors such as inflammation, surgical interventions, and GC therapy may compromise intestinal calcium absorption beyond vitamin D’s influence [92]. To mitigate these risks and effectively manage musculoskeletal health effectively in IBD patients, regular monitoring of serum calcium levels is essential.

3) Vitamin K Deficiency

Vitamin K deficiency is prevalent among IBD patients, affecting approximately 54% of those with CD and 43% with UC. The highest prevalence is observed in pediatric IBD (PIBD) patients [94,95]. This deficiency can arise from several factors, including malabsorption due to intestinal inflammation, impaired bile salt production, and the use of certain medications (e.g., antibiotics) [96]. Low vitamin K status correlates with low BMD of the lumbar spine in patients with longstanding CD, suggesting that vitamin K deficiency may contribute to the development of osteopenia/osteoporosis in these patients [97,98]. Vitamin K deficiency impairs osteocalcin production, which is crucial for bone mineralization and muscle contractility [99,100]. Larger studies assessing bone turnover rates, bone loss, and fracture likelihood are necessary to validate these findings.

4) Magnesium Deficiency

Magnesium is an essential mineral crucial for maintaining normal BMD and muscle contractility [101,102]. Magnesium deficiency directly contributes to osteoporosis by affecting apatite crystal formation and bone cells, and indirectly by disrupting PTH and 1,25(OH)2-vitamin D homeostasis, resulting in hypocalcemia and increased low-grade inflammation. Magnesium deficits can cause physical symptoms like fatigue, muscle cramping, and arrhythmia [103]. Soare et al. [101] demonstrated that low magnesium is a risk factor for low BMD in young IBD patients (pre-menopausal women and men under 50 years). Low magnesium levels directly inhibit osteoblastogenesis while increasing osteoclastogenesis [103,104]. Ensuring adequate magnesium levels through dietary strategies and supplementation can help mitigate the risks of osteoporosis and muscle-related symptoms, thereby improving overall health outcomes for IBD patients. Regular monitoring and proactive management of magnesium levels should be integral parts of the care plan for individuals with IBD.

5) Protein Deficiency

Protein deficiency (20%–85% prevalence) [36] affects both tissues through reduced muscle protein synthesis, potential “anabolic resistance” in IBD patients [69,105], impaired bone matrix formation, and enhanced protein catabolism due to GC use. Several factors contribute to protein deficiency in IBD, including reduced food intake, malabsorption, increased protein losses (protein-losing enteropathy during severe colonic inflammation, blood loss in active disease), and GCs.
Protein deficiency in IBD leads to reduced muscle mass and strength, negatively impacting physical function and quality of life and potentially reducing the efficacy of medical treatments. Tailoring protein intake is crucial based on the disease activity status. During active IBD, protein intake should be increased (1.2–1.5 g/kg/day in adults). During remission, protein intake can be similar to the general population, but with continued monitoring [106].
Anabolic resistance in IBD presents a complex clinical picture, particularly in pediatric populations. Studies have shown that pediatric CD patients, especially males in remission, exhibit decreased protein balance following mixed meals, suggesting reduced muscle protein synthesis in response to dietary protein. This impaired anabolic response may contribute to sarcopenia development [68,105].
However, the evidence regarding anabolic resistance in IBD remains inconclusive. Davies et al. [107] found comparable muscle mass, function, and metabolic markers between CD patients and healthy controls. The relationship between inflammation and metabolic disturbances in IBD appears nuanced. Active inflammation may promote insulin resistance and metabolic dysregulation, however, achieving remission can normalize insulin sensitivity [108]. The absence of metabolic disturbances during remission suggests that additional factors influence the development of anabolic resistance in CD patients.
Given these complexities, meeting increased nutritional demands becomes crucial for managing inflammation and preserving muscle mass in IBD patients [68,105]. Treatment strategies should emphasize adequate protein and energy intake to counteract catabolic processes, targeted nutritional strategies to address potential anabolic resistance, and optimization of overall nutritional status. Further research is required to elucidate the mechanisms underlying anabolic resistance and insulin sensitivity in IBD.
3. Physical Inactivity
Physical inactivity in IBD patients is driven by disease symptoms fatigue, and psychological barriers [109,110]. During active disease, symptoms such as abdominal pain, frequent bowel movements, low body mass index (BMI), low vitamin D3, and elevated C-reactive protein (CRP) restrict physical activity [111], initiating a cascade of detrimental effects on the musculoskeletal system. Although remission typically enables increased physical activity in IBD patients, certain individuals, particularly pediatric patients, continue to face barriers. These obstacles include residual fatigue, deconditioning, fears of exercise exacerbating symptoms, and insufficient guidance from healthcare providers [112-115]. Notably, females and children with IBD are more likely to have lower physical activity levels [116-118]. Female CD patients are especially vulnerable to lean mass (LM) and fat mass (FM) deficits [119].

1) Impact of Reduced Physical Activity

In bone tissue, decreased mechanical loading diminishes osteoblast activation and bone formation through mechanotransduction pathways. Simultaneously in muscle, physical inactivity triggers decreased protein synthesis and increased proteolysis, particularly affecting type II muscle fibers. This creates a detrimental cycle where muscle weakness further discourages physical activity, accelerating overall musculoskeletal deterioration [120].

2) Molecular Mechanisms of Exercise Benefits

During exercise, osteocytes in bone, detect mechanical forces through focal adhesions and integrins, transmitting signals to osteoblasts, osteoclasts, and the bone microenvironment that promote bone formation. This mechanotransduction involves several key mechanisms: exercise-induced ATP release activating purinergic receptors, mechanosensitive channels (including polycystins) stimulating osteoblast activity, and downregulation of sclerostin through the Wnt/β-catenin pathway [121]. The RANKL/OPG system further modulates osteocyte responses to mechanical stimulation.
In muscle tissue, exercise enhances myogenic potential, contractile function, and satellite cell activity while optimizing muscle regeneration [122]. Additionally, exercise beneficially modifies intramyocellular lipid composition and reduces age-related intermuscular fat accumulation. These adaptations, combined with improved insulin sensitivity and mitochondrial function, appear to be mediated through enhanced neuromuscular activation and vascular function [122].
Evidence suggests that combining aerobic and strength training exercises safely improves body composition through increased muscle mass and decreased FM [109]. Importantly, increased physical activity is associated with better disease outcomes and reduced illness severity specifically in CD patients. This association is not observed in UC patients, suggesting different mechanisms by which physical activity influences disease activity and symptoms in CD versus UC [116,123].
To optimize health benefits, IBD patients should engage in a comprehensive exercise program that includes aerobic exercises, strength training, flexibility exercises, and balance training. Moderate exercise programs can be beneficial for IBD patients with low and well-controlled disease activity.
4. Hypogonadism
Hypogonadism in IBD significantly impacts both bone and muscle health through several pathways. Chronic inflammation suppresses the hypothalamic-pituitary-gonadal axis, reducing sex hormone production. The resulting decrease in testosterone and estrogen creates direct catabolic effects on both tissues, contributing to osteosarcopenia in IBD patients [124,125].
In bone tissue, sex hormone deficiency increases osteoclast activity while impairing osteoblast function. In muscle tissue, particularly in male patients, low testosterone levels reduce protein synthesis and muscle fiber maintenance. This hormonal disruption favors tissue breakdown over formation, accelerating osteosarcopenia development.
Pediatric CD patients with high disease activity show declining testosterone levels [126]. Pro-inflammatory cytokines suppress testosterone production, often resulting in delayed puberty [126]. This combination of hypogonadism and delayed puberty leads to impaired bone development and increased osteoporosis risk later in life [127-129].
The relationship between hypogonadism and bone health shows some variability in research findings. While some studies demonstrate a correlation between dehydroepiandrosterone sulfate and BMD at the femoral neck and lumbar spine, others have not found clear associations between testosterone levels and bone parameters in men with IBD [130-132].
Estrogen receptor-β maintains intestinal epithelial architecture under normal conditions [133]. Patients with active IBD show lower estrogen receptor-β expression compared to those in remission and healthy controls [134]. Estrogens protect bone health by inhibiting osteoclast activity through the Wnt-β-catenin and OPG/RANKL pathways [135]. In estrogen-deficient conditions, IL-6 can stimulate osteoclast formation and affect muscle and fat metabolism [136].
Treatment considerations include hormone replacement therapy for IBD patients with hypogonadism and osteoporosis: testosterone for men and estrogen-progestin for pre-menopausal women [137]. Testosterone therapy in CD has shown improvements in disease course [138].
The complex interplay between hypogonadism and osteosarcopenia in IBD emphasizes several key points: the importance of early detection of hormonal imbalances, the need for interventions tailored to age, sex, and IBD type, and the requirement for long-term studies evaluating hormone replacement therapy outcomes in IBD patients.
5. Glucocorticoids
While these pathophysiological mechanisms represent direct disease effects, therapeutic interventions, particularly GCs, introduce additional complexity to musculoskeletal health in IBD. As a first-line treatment for inducing remission in active IBD, GCs suppress the production of pro-inflammatory cytokines, inhibit T-cell proliferation, NF-κB expression, and induce anti-inflammatory proteins like lipocortin-1, IL-1 receptor antagonists, and Iκ-B [139]. UC patients typically have higher GC exposure compared to CD patients (10.7% vs. 6.8%) [84,140,141].
GCs exert widespread systemic effects that simultaneously impact both bone and muscle integrity, creating a synergistic deterioration of musculoskeletal health. In bone-muscle unit, GCs create a dual assault: they enhance osteoclast survival while impairing osteoblast function, and simultaneously trigger muscle protein degradation while suppressing protein synthesis. This coordinated disruption accelerates tissue loss and compromises both bone microarchitecture and muscle function, substantially increasing fracture risk [142,143].
The molecular mechanisms underlying these effects are complex. In bone tissue, GCs upregulate RANKL expression while reducing OPG receptors in osteoblastic cells. They inhibit osteoblast differentiation, induce apoptosis, promote osteoclast differentiation, and reduce osteoid matrix secretion. Although the RANKL increase is transient, the long-term detrimental effects primarily stem from suppressed bone formation rather than increased resorption [144]. GCs further impact bone metabolism by disrupting vitamin D metabolism, altering PTH regulation, and interfering with calcium homeostasis through reduced intestinal absorption and increased renal loss [135,145,146].
Long-term GC use reduces calcium absorption in the intestines while increasing calcium loss through the kidneys and bones [147]. These combined effects make GCs a significant risk factor for low BMD, osteoporosis, and fractures, particularly in vulnerable populations like children with prolonged exposure and elderly patients [85,142,148-151].
Interestingly, some studies show that bolus tapering of methylprednisolone over 12 weeks can maintain bone density and improve body fat distribution in IBD patients [152]. In certain cases, GCs may not directly correlate with reduced BMD, suggesting that factors like disease activity, malnutrition, and vitamin/mineral deficiencies may also contribute to bone loss in IBD patients [10].
In muscle tissue, GCs particularly target type II muscle fibers, diminishing strength and function [143]. Long-term GC therapy (more than 3 months) reduces muscle mass and function, potentially through IGF-1 suppression and myostatin induction [47,153]. The combined effect creates a vicious cycle where weakened muscles provide inadequate support for compromised bone structure.
These effects are particularly concerning in specific populations. Children face additional challenges as GCs can delay puberty through hypogonadotropic hypogonadism, affecting both muscle mass development and bone mineralization [47,153]. Short-term GC therapy in newly diagnosed pediatric CD increases muscle protein breakdown, while long-term use impairs lean body mass acquisition, BMD, and adult height attainment [53]. Avascular necrosis of the hip occurs in 9% to 40% of IBD patients receiving long-term GC therapy [154].
Consequently, the use of GCs in patients with IBD, particularly in pediatric cases, should be minimized whenever possible. If necessary, their use should be closely monitored and tapered as quickly as clinically feasible to reduce the risk of growth and pubertal disturbances, as well as adverse effects on muscle mass and function.
To mitigate these adverse effects, several strategies are recommended: implementing regular weight-bearing exercises, ensuring adequate nutrition with calcium and vitamin supplementation, and considering injectable bisphosphonate for patients at moderate-to-high fracture risk [146,155,156]. To mitigate these adverse effects, several strategies are recommended: implementing regular weight-bearing exercises, ensuring adequate nutrition with calcium and vitamin supplementation, and considering injectable bisphosphonate for patients at moderate-to-high fracture risk [139].
This complex interplay between GC therapy and musculoskeletal health emphasizes the need to minimize GC use, particularly in pediatric cases. When necessary, GC treatment should be closely monitored and tapered as quickly as clinically feasible to reduce adverse effects on growth, puberty, and musculoskeletal integrity [143].
1. Prevalence and Demographics
The musculoskeletal burden in IBD manifests through significant rates of both bone and muscle deterioration. The prevalence of osteoporosis ranges from 13% to 42% in IBD patients [157], while osteopenia rates reach up to 77% of cases [158]. A meta-analysis comparing 232 IBD patients to 199 non-IBD controls found osteoporosis in 7.3% of IBD cases [159]. Among newly diagnosed IBD patients, 24.6% presented with osteopenia, while 5.4% already had osteoporosis [160], highlighting early musculoskeletal involvement in the disease process.
Parallel to bone deterioration, muscle health is significantly compromised in IBD patients. Studies reveal high sarcopenia rates using various assessment methods: 50% prevalence using ultrasound muscle index (≤21.9 mm/hr2) [161] and 64.7% based on skeletal muscle index (SMI) thresholds [162]. This muscle deterioration appears early, with approximately 50% of newly diagnosed CD patients exhibiting sarcopenia [163]. The condition affects 52% of CD patients and 37% of UC patients [119]. A comprehensive analysis of 35 studies (2,770 CD and 1,473 UC adult patients) revealed that 42% exhibited myopenia (45% of CD and 43% of UC) (measured by low muscle mass), 34% showed pre-sarcopenia (by low hand grip strength) (35% in CD patients and 32% in UC), and 17% had developed sarcopenia (12% in CD patients and up to 14% in UC) combining low muscle mass and strength [164]. Further research on UC patients specifically identified varying degrees of muscle compromise: 37.7% had probable sarcopenia (reduced grip strength), 21.9% had sarcopenia (reduced grip strength and muscle mass), and 12.2% had severe sarcopenia (reduced grip strength, muscle mass and physical performance) [165]. Low grip strength (<16 kg for females and <27 kg for males) correlates with increased hospitalization, likely due to systemic inflammation, metabolic alterations, muscle deterioration, and impaired physical function [166].
The molecular basis for reduced grip strength involves multiple factors: low IGF-1 and myostatin levels, CD-induced inflammation, and p38 MAPK signaling limitations affecting myogenesis and muscle regeneration [167]. While grip strength assessment primarily reflects upper limb muscle strength, leg muscles often show greater vulnerability due to reduced daily activity [168,169]. Studies on lower limb muscular strength in adult IBD patients yield mixed results [170]: reduced strength in CD patients in remission with prior small bowel resection [88], decreased function in both fatigued and non-fatigued CD/UC patients in remission [168], weakness in sedentary female UC patients across disease activities [168]; specific deficits in knee flexors (longstanding CD) [171] and extensors (CD patients in both remission and active disease) [172]. Notably, recently diagnosed CD/UC patients showed no strength differences compared to healthy controls, and CD patients maintained similar strength levels in both remission and active disease states [49,171].
Sex-specific patterns add complexity to this musculoskeletal deterioration. Meta-analyses revealed inconsistent findings regarding sex-specific differences in osteoporosis risk [173]. While some studies found no significant sex [174], others reported that male IBD patients face osteoporosis risks comparable to postmenopausal women [175]. These sex variations likely stem from differences in hormonal profiles, genetic factors, and gut microbiome composition [176,177].
Age introduces another dimension to the musculoskeletal manifestations of IBD. Notably, IBD patients develop sarcopenia at younger ages compared to the general population [178], though rates increase in older patients, particularly those with comorbidities like hypertension and diabetes [179]. Even with effective disease management, muscle deficits can persist. Young adults with well-managed childhood-onset CD show ongoing deficiencies in muscle area, mass, function, and strength, despite normal bone parameters [143].
The pattern of musculoskeletal deterioration shows important sex-specific considerations (Table 2) [84,126,173,180-192]. Male patients demonstrate a higher sarcopenia risk [7,178,193], while female CD patients require monitoring for persistent muscle deficits [194,195]. Additionally, underweight female patients show increased sarcopenia frequency [196]. In conclusion, this integrated view of muscle and bone deterioration in IBD reveals the need for comprehensive assessment strategies that consider the concurrent nature of bone and muscle loss, sex-specific patterns of deterioration, age-related variations in presentation, disease subtype influences and the impact of nutritional status. Understanding these patterns enables more targeted interventions and monitoring strategies for IBD-related musculoskeletal complications.
2. Bone Metabolism Dysregulation in PIBD
PIBD patients exhibit compromised bone health, with 75% to 89% showing low areal BMD during active disease and 10% to 37% during remission [197]. CD disrupts normal bone development during critical growth periods, potentially reducing (20%–50%) peak bone mass attainment [198-202]. Newly diagnosed PIBD patients frequently present with weight loss and decreased bone mass. These factors contribute to growth delay, impaired peak bone mass attainment, and increased risk of osteoporosis and fractures in adulthood [198-201,203]. Notably, growth failure affects male children with CD more frequently [197]. Pediatric UC cases rarely experience growth failure (0%–10%) [204]. CD compromises bone health through a complex interplay of mechanisms: inflammatory mediators, low nutrient intake, malabsorption, and GC therapy [203,205]. These disturbances have profound consequences: reduced bone mass accrual, altered bone structure, increased fracture risk, growth retardation, and delayed pubertal development. Specifically, CD may lead to decreased cortical thickness, increased cortical porosity, thinning of trabeculae and a reduced trabecular number. These changes compromise the internal architecture of bones, elevating skeletal vulnerability [115,197,200]. Research suggests that individuals with CD often have higher cortical bone density in long bones (e.g., femur and tibia) at diagnosis, potentially attributed to a decreased rate of bone remodeling [206,207]. This phenomenon illustrates how CD disrupts bone homeostasis early, even before severe bone mass and quality deficits become apparent. The initial higher cortical density may give way to overall bone loss and structural changes. As CD progresses, more severe deficits in bone mass and quality may develop. Encouragingly, BMD may return to normal levels after approximately 3 years of disease remission in IBD patients [208,209]. This suggests that some detrimental effects of IBD on bone health could be reversible with effective long-term management.
Skeletal muscle exhibits high metabolic activity, characterized by rapid protein turnover rates surpassing those of bone. This enables swift adaptations to exercise, nutrition, hormonal fluctuations, and IBD processes. In contrast, changes in BMD, geometry, and microarchitecture occur more gradually due to the longer lifespan of osteoblasts and osteoclasts. Pediatric CD studies illustrate these distinct temporal patterns. Research in PIBD reveals a link between low muscle Cross section area (CSA) and poor trabecular BMD and cortical thickness [206,210]. Although muscle mass and trabecular BMD improve partially after 1 year, persistent cortical bone deficits highlight the need for targeted interventions addressing both muscle and bone health [206]. Compensatory mechanisms, such as increased cortical bone CSA, cannot fully offset muscle deficits from low muscle CSA [210]. Reduced LM compromises muscle force generation, disrupting bone remodeling and mechanical stress [211]. Even well-managed CD patients show deficits in muscle area, mass, function, and strength despite maintaining normal bone microarchitecture and geometry at the distal femur [167]. The high metabolic activity and rapid adaptability of skeletal muscle necessitate long-term monitoring to assess bone health changes in PIBD [212].
The primary concern in PIBD is often the failure to achieve peak bone mass due to impaired bone formation rather than accelerated bone loss. In pediatric CD, there is often a marked suppression of bone formation, evidenced by low levels of osteocalcin and bone-specific alkaline phosphatase. This is particularly crucial as it occurs during a vital period of bone mass accrual [213]. Interestingly, some studies suggest that while low bone formation in PIBD, bone resorption rates may remain normal compared to healthy controls [214,215].
Unlike in PIBD, adults with IBD typically show increased bone resorption. The combination of low bone formation and high bone resorption in adult IBD patients leads to a more rapid net bone loss [216]. Several factors may contribute to this difference, including the developmental stage: children’s bones are in a phase of rapid growth and formation, making them more sensitive to disruption [200]. In contrast, adult bones have completed growth, so the balance shifts more towards maintenance and remodeling. Additionally, children are often newly diagnosed, while adults may have had IBD for years, allowing for cumulative effects on bone metabolism. Adult patients may also experience longer exposure to medications that affect bone metabolism, particularly GCs [217]. The chronicity of inflammation in adult IBD may further exacerbate osteoclast activation [218]. While this general pattern exists, it is important to note that there can be significant individual variation. Some PIBD patients may exhibit increased bone resorption [219,220], while some adults may primarily show low bone formation [221] or suppressed bone resorption [222]. Histomorphometry analysis of transiliac bone biopsies in children with newly diagnosed CD displayed suppressed bone formation (osteoblastogenesis) and enhanced bone resorption (osteoclastogenesis) [200]. This imbalance in bone metabolism with uncoupling of bone cell activities, favoring resorption over formation, suggests that bone metabolism disruption is an early consequence of CD pathophysiology.
These early metabolic disturbances manifest in complex fracture risk patterns among PIBD patients. The clinical picture is complicated by multiple factors including disease duration, severity, geographic location, and treatment regimens. Evidence regarding fracture risk shows considerable variation: while some studies indicate low fracture risk [126,223,224], others report rates comparable to the general pediatric population [125,178,225,226], with notably increased vertebral abnormalities [226]. A few studies highlight an elevated fracture risk in PIBD patients [83,225]. On the contrary, different study revealed that growth inhibition is rarely a problem in children with UC (0%–10%) [195].
Age emerges as a critical factor in fracture risk assessment. Children under 12 years old with IBD have an elevated risk of fracture compared to their non-IBD peers. However, this increased fracture risk is not observed in older children [227,228]. Yang [83] found that children with IBD treated with GC had an increased risk of bone fractures. Specifically daily GC dose exceeding 7.5 mg, lifetime cumulative dose greater than 5 g, or lifetime exposure exceeding 12 months were associated with increased fracture rates. These findings emphasize the need to carefully balance GC treatment benefits against potential bone health risks.
The heterogeneity of bone metabolism disturbances across age groups necessitates tailored treatment approaches. PIBD patients require strategies focused on promoting bone formation and ensuring adequate growth, while adults often need interventions addressing both decreased formation and increased resorption. Without appropriate management, these disruptions in bone metabolism can lead to low bone mass (osteopenia or osteoporosis), with potential alterations in bone microarchitecture [206,207,229].
3. Fracture Risk in IBD
These metabolic disruptions translate into significant fracture risks that persist into adulthood. IBD patients face a markedly elevated risk for spinal fractures, exceeding the general population by more than 38%, which emphasizes the importance of proactive osteoporosis management [33]. Hip fractures show particularly concerning rates. IBD patients have approximately 60% higher risk of hip fractures [230]. Vertebral fractures are observed in 7% of IBD cases, while non-vertebral fractures occur in 24% to 27% of patients [174].
CD patients have a more pronounced risk, with an 86% higher incidence (relative risk, 1.4–2.5), while UC patients show a 40% higher incidence (relative risk, 1.2) [223,225,230,231]. Sex-specific analyses present mixed findings: some evidence indicates higher low-trauma fracture risk specifically in females with CD, while other data suggests equal risk distribution between males and females with IBD [224,226]. However, the relationship between IBD and fracture risk remains complex, as some studies suggest that IBD may not independently increase overall fracture risk when controlling for other variables [227,228,232,233]. These findings emphasize the importance of comprehensive fracture risk assessment and regular bone health monitoring in routine IBD care, particularly for patients with additional risk factors or recent diagnosis.
The relationship between muscle health and fracture risk becomes evident in newly diagnosed patients, where both bone fragility and muscle deterioration manifest early in the disease course [234]. Ahn et al. [234] demonstrated an elevated risk of vertebral and hip fractures in newly diagnosed IBD patients, particularly in early CD cases, independent of initial GC exposure. This concurrent deterioration emphasizes the need for integrated musculoskeletal assessment from diagnosis.
4. Body Composition Changes
The intricate relationship between muscle and bone health manifests through body composition changes. Sarcopenia serves as a predictor of osteoporosis in IBD patients, with consistent correlations between low muscle mass and decreased bone density [14,235,236]. The underlying mechanism involves reduced LM compromising muscle force generation, diminished mechanical stress on bones, leading to imbalanced bone remodeling [212].
Disease-related changes in body composition include LM and FM alterations and complex metabolic alterations. LM deficits affect up to 93.6% of CD and 48% of UC patients [237]. Low LM predicts disease activity in CD patients [238]. Changes impact physical function, metabolism, and BMD [211]. Metabolic alterations occur due to chronic inflammation, malabsorption, pro-inflammatory cytokines, surgical interventions and GC therapy. These factors can lead to sarcopenic obesity, abdominal adiposity, paradoxical fat accumulation despite malnutrition [116,208,239-241].
5. Clinical Outcomes and Surgical Implications
The impact of musculoskeletal deterioration extends to surgical outcomes. Sarcopenia predicts surgical intervention needs [242]. Up to 80% of CD patients may require surgery [192,243]. Sarcopenic IBD patients are more vulnerable to hospitalizations, disease flares, and colectomy [7,14,244-247]. Low muscle mass (SMI/skeletal muscle area) increases surgical risk [32,247,248]. Bamba et al. [249] found that muscle volume affects short-term outcomes, hospital stay duration, and long-term outcomes, including intestinal resection. Pozios et al. [250] asserted that neither sarcopenia nor myosteatosis was associated with clinically relevant postoperative complications [61]. Interestingly, Adams et al. [7] claimed that a significant correlation between sarcopenia and surgery was observed only in overweight IBD patients.
Medical management and surgery can improve muscle mass and body composition in UC [178,251]. CD patients show partial SMI recovery after intestinal resection. Body composition during remission may approach normal, while BMD changes occur gradually. This integrated understanding emphasizes the need for early musculoskeletal assessment, regular monitoring of both muscle and bone health, consideration of body composition in treatment planning, prevention strategies targeting both tissues, and long-term follow-up of musculoskeletal outcomes.
6. Screening Protocol and Risk Stratification
Screening protocol: Clinical presentation often includes subtle manifestations that can be overshadowed by primary IBD symptoms, necessitating heightened vigilance among healthcare providers. Notably, bone and muscle loss may precede obvious gastrointestinal symptoms in IBD patients [252,253]. The diagnosis requires multiple factors unique to IBD patients, distinguishing it from age-related cases.
The implementation of a systematic screening protocol is essential for early detection and effective management of osteosarcopenia in IBD. Fig. 3 illustrates the systematic screening and monitoring protocol for IBD-associated osteosarcopenia, from initial diagnosis through long-term follow-up. This algorithm ensures standardized assessment and appropriate intervention based on individual risk profiles.
Upon initial IBD diagnosis, patients should undergo risk stratification to determine the timing and intensity of screening. High-risk individuals, characterized by severe disease activity, malnutrition (BMI <18.5 kg/m2), significant steroid exposure >3 months, or age >60 years, warrant immediate comprehensive assessment. For standard-risk patients, initial screening should be completed within 6 months of diagnosis, establishing a baseline for long-term monitoring.

1) Monitoring Frequency and Special Considerations

Monitoring frequency is determined by individual risk profiles, with high-risk patients requiring annual comprehensive assessments, semi-annual clinical reviews, and disease activity monitoring every 3 to 4 months. Standard-risk patients may follow a less intensive schedule, with comprehensive assessments every 2 years and annual clinical reviews. Special considerations apply to pediatric groups. PIBD patients require more frequent monitoring during growth periods, with threshold adjustments for the pubertal stage. Elderly patients need additional attention, including fall risk assessment every 6 months, quarterly balance and mobility evaluation, annual cognitive function screening, and regular medication review for fall risk factors.

2) Assessment and Diagnostic Thresholds

The core screening protocol integrates 3 essential domains: bone health, muscle status, and comprehensive clinical evaluation. These components work together to provide a complete assessment of osteosarcopenia risk in IBD patients. Fig. 4 provides a detailed framework for the comprehensive assessment of both bone and muscle health parameters. This systematic approach ensures thorough evaluation of structural, functional, and biochemical aspects of musculoskeletal health in IBD patients.

3) Bone Health Assessment

Bone health assessment begins with dual-energy X-ray absorptiometry (DXA) scanning at weight-bearing skeletal sites such as the lumbar spine, femoral neck, and total hip [254-256]. Standard diagnostic criteria define osteoporosis as a T-score ≤ –2.5, while osteopenia represents an early stage of bone loss where BMD is lower than normal (T-score between –1 and –2.5) [6]. However, the intervention threshold in IBD patients should be adjusted to T-score –2.0 when additional risk factors are present, particularly in cases of active inflammation (CRP >5 mg/L), repeated steroid exposure, or disease duration exceeding 10 years. The American Gastroenterological Association guidelines recommend DXA screening for IBD patients with specific risk factors, including postmenopausal women, elderly men (>50 years), chronic GC therapy, hypogonadism, history of bowel resections and previous vertebral fractures [257]. Additionally, Adriani et al. [221] proposed that DXA should be performed in men aged >30 years and in all women among newly diagnosed IBD patients.

4) Special Considerations for Pediatric Patients

PIBD patients require distinct assessment criteria, including exclusive use of Z-scores rather than T-scores, adjustments for pubertal stage, growth velocity, and skeletal maturation. DXA screening is recommended for those with growth failure, BMI <2nd percentile, primary or secondary amenorrhea, severe inflammatory disease, and more than 6 months of GC therapy [200,258-260].

5) Advanced Imaging and Biomarker Assessment

DXA scans alone may not capture all aspects of bone health, particularly in cases of normal BMD but altered bone microstructure. Additional assessment methods include advanced imaging high-resolution peripheral computed tomography and quantitative computed tomography for detailed examinations of trabecular and cortical bone microstructure [188,254] and magnetic resonance enterography for muscle mass evaluation [261].
This is complemented by the evaluation of biomarkers. Traditional inflammatory markers such as CRP, TNF-α, and erythrocyte sedimentation rate must be evaluated alongside bone turnover markers and muscle-specific indicators. Biomarkers of bone turnover are C-terminal telopeptide of type I collagen (β-CTX), procollagen type 1 N propeptide (P1NP), and N-terminal telopeptide of type I collagen (NTX), PTH for bone resorption and alkaline phosphatase, vitamin D and osteocalcin for bone formation [86,159,256,262]. De Voogd et al. [263] proposed OPG as a non-invasive biomarker for inflammation in IBD patients. However, OPG levels show variable responses in bone [57-59,264]. The relationship between these biomarkers and disease activity adds another layer of complexity to diagnosis, as fluctuations may reflect both IBD activity and musculoskeletal deterioration.

6) Muscle Assessment and Population-Specific Criteria

Muscle mass and function evaluation requires a multimodal approach combining quantitative measurements: SMI via computed tomography scans at L3 vertebra and population-specific thresholds for non-Asian populations 52.4–55 cm2/m2 (men), 38.5–39 cm2/m2 (women) [7,192,248,251] and for Asian populations: <49 cm2/m2 (men), <31 cm2/m2 (women) [184,187]. A recent study by Mulinacci et al. [161] established ultrasound as an effective diagnostic tool for sarcopenia in IBD, demonstrating 100% sensitivity. It has been reported that serum concentrations of myostatin and activin A may provide valuable diagnostic markers for identifying sarcopenia in its early stages among IBD patients [265].
Functional evaluations of muscle include hand grip strength, 4-m gait speed, and the 5-repetition chair stand test. Grip strength thresholds should be adjusted during active disease periods, with normal values set at >27 kg for men and >16 kg for women. During active disease, these thresholds should be reduced by approximately 10%. Physical performance metrics, such as gait speed, maintain the standard threshold of ≥0.8 m/s for normal function, but interpretation should consider the impact of active disease on performance.

7) Intervention Triggers

Clear intervention triggers have been established to guide clinical decision-making, including T-scores ≤–2.5 (or Z-scores ≤ –2.0 in younger adults 18–40 years), low muscle mass combined with reduced function, significant decline between assessments, new fracture occurrence, disease flares requiring steroid therapy, and significant nutritional compromise. This comprehensive approach ensures systematic evaluation and appropriate intervention timing for IBD patients at risk of osteosarcopenia.
The implementation of treatment for osteosarcopenia in IBD patients requires a carefully structured approach combining both non-pharmacological and pharmacological interventions, with regular monitoring to ensure optimal outcomes. Non-pharmacological interventions, which form the foundation of treatment for all risk levels, include progressive resistance training, balance exercises, and nutritional optimization with adequate protein intake (1.2–1.5 g/kg/day) and vitamin D supplementation. These interventions are complemented by pharmacological treatments, which are tailored based on the patient’s risk level and specific deficits identified during assessment. For patients with severe bone loss, antiresorptive agents such as bisphosphonates may be prescribed, while those with significant muscle weakness might benefit from vitamin D supplementation, particularly if deficient. The effectiveness of these interventions requires regular monitoring through periodic assessments of BMD, muscle strength, and functional capacity, typically every 6 to 12 months. Treatment adjustments are made based on these monitoring results, considering factors such as disease activity, medication side effects, and patient compliance. The monitoring process should also include screening for falls risk and assessment of nutritional status, allowing for timely modifications to both non-pharmacological and pharmacological interventions to optimize treatment outcomes.
1. Non-Pharmacological Management
Nutrition optimization and regular physical activity, combined with lifestyle modifications, can synergistically enhance the effectiveness of pharmacological treatments (Fig. 5). This integrated approach promotes both bone and muscle health while helping to regulate inflammatory pathways [28]. This multimodal approach capitalizes on treatment synergies, demonstrating superior outcomes for musculoskeletal health compared to monotherapy.
2. Nutritional Therapies
Optimal nutritional support is fundamental to PIBD management, with critical significance during active disease phases [266]. Adequate intake of calcium, vitamin D, and vitamin K is crucial for supporting bone health, while protein helps maintain muscle mass. Additionally, whole foods rich in omega-3 fatty acids, fiber, and antioxidants contribute to overall well-being. Tailoring protein intake is crucial based on the disease activity status. During active IBD, protein intake should be increased (1.2–1.5 g/kg/day in adults). During remission, protein intake can be similar to the general population with continued monitoring [106]. “Calcium and vitamin D supplementation may not significantly improve BMD in PIBD when baseline nutritional intake is adequate [267,268]. Some PIBD patients show low BMD at the lumbar spine despite adequate vitamin D intake, possibly due to poor absorption [228].
Early initiation of nutritional therapy as well as regular assessment of the nutritional status of IBD patients at risk is beneficial [269]. Notably, linear growth recovery is more pronounced in patients receiving nutrition therapy compared to those treated with GCs. Furthermore, a significant number of patients in the GC-treated group (90%) experienced adverse events, including muscle weakness, whereas the nutrition therapy group had fewer adverse events [270]. It is important to maintain a balanced gut microbiome through prebiotics and probiotics. Probiotic treatment of IBD patients may be beneficial to reduce intestinal inflammation and permeability [271,272]. Although further studies are needed to confirm the benefits of probiotics, this approach shows promise in alleviating IBD symptoms.
Moreover, optimizing nutritional status before surgery is crucial for IBD patients. Notably, pre-operative skeletal muscle percentage is a significant independent protective factor against postoperative major complications in severely malnourished CD patients [273]. Therefore, pre-operative nutritional support is provided before intestinal resection [273]. Pre-operative intravenous total parenteral nutrition administration induces remission and reduces postoperative complications in malnourished sarcopenic CD patients [273,274]. These novel dietary interventions have shown efficacy in inducing remission in pediatric CD patients, offering a more diverse and potentially better-tolerated option for managing the condition. In PIBD, exclusive enteral nutrition (EEN) serves as a valuable therapeutic intervention, effectively promoting normal pubertal development, linear growth, and optimal body composition. EEN’s dual mechanism of providing comprehensive nutritional support while attenuating inflammation helps counteract IBD-related growth and developmental impairments [275]. An 8-week course of EEN has been shown to improve serum markers of bone formation while decreasing markers of bone resorption [276]. EEN followed by partial enteral nutrition resulted in better BMD outcomes compared to GC therapy [277]. Additionally, a 12-week EEN course significantly increased trabecular and cortical bone density in children with newly diagnosed CD [275]. When combined with infliximab (IFX), EEN demonstrated similar short-term efficacy in improving BMI in pediatric CD patients [278]. However, long-term adherence to EEN is often challenging due to its monotony and low tolerance among PIBD patients. In response, innovative dietary approaches, such as CD exclusion diet have emerged [279]. Combining EEN with a CD exclusion diet (a wholefood diet with partial enteral nutrition) induce sustained remission more effectively than EEN alone [280,281]. While nutritional optimization is crucial for managing sarcopenia in IBD, the role of specific dietary interventions and supplements is understudied. Further research, particularly in adult IBD populations, is essential to refine these strategies and bridge existing knowledge gaps.
3. Physical Activity and Exercise
Studies emphasize the importance of addressing modifiable risk factors, such as physical inactivity to prevent osteoporosis in IBD patients [159,282,283]. Engaging in regular tailored physical activity is crucial for mitigating musculoskeletal wasting associated with IBD and sedentary lifestyle. This is especially vital for PIBD patients, who are in a critical phase of physical growth and development [284]. Daily activities such as walking, housework, or light gardening help maintain basic muscle function, contribute to overall energy expenditure, and reduce the risks associated with sedentary behavior [284]. In UC patients, increased physical activity is linked to lower fatigue, improved disease activity, better sleep, and reduced anxiety [284]. Even a modest increase in physical activity from a sedentary baseline is beneficial. For some IBD patients, especially during active disease phases, starting with small daily activities may be the first step before progressing to more structured exercise routines. Structured exercise programs tailored to the individual’s condition and capabilities are necessary for optimal muscle and bone health in IBD patients. These programs should ideally include a combination of weight-bearing, resistance, and aerobic exercises. The British Society of Gastroenterology recommends exercise to prevent and treat osteoporosis in IBD patients [150]. An ideal exercise program combines aerobic, resistance, flexibility and balance training. Weight-bearing exercise provides beneficial mechanical loading to stimulate osteoblast activity and bone formation. Low-magnitude mechanical stimulation (e.g. vibration platforms) may have anabolic effects on bone in IBD [199]. Studies suggest that exercise enhance fitness, BMD, muscle mass, and strength in IBD patients without exacerbating symptoms, particularly in mild-to-moderate cases [283]. Several studies have demonstrated the benefits of tailored exercise programs for IBD patients. A 6-month home-based structured exercise program for children and adolescents with IBD led to significant improvements in BMD and lean body mass [285]. An 8-week progressive resistance training program improved quadriceps muscle strength and quality of life among females with IBD, with strength gains attributed to neural adaptation rather than muscle hypertrophy [286]. Regular, moderate-intensity exercise has also shown anti-inflammatory effects, which can help in managing IBD [287]. Additionally, exercise can positively influence the course of IBD by reducing symptom severity and prolonging remission periods [116]. For patients with quiescent CD, exercise enhances muscle strength and endurance through the release of myokines, which improve insulin sensitivity and glucose uptake while inhibiting inflammatory factors [288]. While acute exercise may transiently elevate some inflammatory markers in younger CD patients, it is generally considered safe [289]. Interestingly, Baker et al. [287] found that exercise did not significantly alter inflammatory markers in IBD patients. However, the unpredictable nature of IBD flare-ups can make maintaining a regular exercise routine challenging [116]. More research is needed to develop comprehensive and safe exercise guidelines for CD patients [290]. Given the critical impact of malnutrition and inactivity on growth and development in PIBD patients, promoting physical activity and monitoring nutritional status are essential components of comprehensive care [69].
4. Lifestyle Modifications
Lifestyle modifications form a crucial foundation in managing IBD-associated osteosarcopenia. Lifestyle modifications encompass various aspects of daily living, including dietary optimization, structured physical activity, and behavioral adaptations. Smoking cessation represents a key intervention, as tobacco use not only exacerbates IBD symptoms but also accelerates bone loss and impairs muscle protein synthesis. Additionally, smoking can interfere with calcium absorption and reduce the effectiveness of IBD medications. Sunlight exposure, when safe and appropriate, can assist with vitamin D synthesis, although it must be balanced against the risks of excessive sun exposure. Fall prevention strategies become essential, particularly in patients with compromised bone density or muscle strength. These strategies include home safety assessments, proper lighting installation, removing trip hazards, and using assistive devices when necessary. Regular physical activity, tailored to individual capabilities and disease status, should be encouraged to maintain muscle mass and bone density. However, activity recommendations must be flexible and adaptable to accommodate disease flares. During periods of active disease, low-impact activities may be more appropriate, with gradual progression to more challenging exercises during remission. Stress management techniques may also be beneficial, as chronic stress can contribute to inflammation and potentially worsen both IBD symptoms and osteosarcopenia. Incorporating mindfulness practices, cognitive-behavioral therapy, deep breathing exercises, progressive muscle relaxation, consistent sleep schedule or other stress-reduction techniques could be part of a comprehensive management plan. Patient education plays a vital role in implementing these modifications, emphasizing the connection between lifestyle choices and musculoskeletal health. Regular monitoring and reinforcement of these lifestyle changes during clinical visits help ensure long-term adherence and optimal outcomes.
5. Pharmacological Interventions for IBD-Associated Osteosarcopenia
Treatment strategies for IBD-associated osteosarcopenia require a multi-targeted approach addressing both bone and muscle deterioration while managing underlying inflammation. Therapeutic interventions combine anti-inflammatory agents targeting systemic inflammation, bone-specific treatments regulating metabolism and hormonal therapies addressing underlying imbalances (Fig. 6). Interventions using pharmacological approach for osteosarcopenia in IBD is advantageous in providing targeted action on specific pathways, potentially rapid effects and can address severe cases effectively. Considerations for pharmacological management include individualized approach, regular monitoring and drug interactions. Treatment should be tailored based on IBD subtype, disease activity, and specific osteosarcopenia characteristics. Potential interactions between IBD medications and osteoporosis treatments should be considered.
6. Anti-Inflammatory Therapy Impact on Musculoskeletal Health
Management of IBD-associated osteosarcopenia requires a dual approach: treating the underlying inflammatory disease while addressing its musculoskeletal manifestations. Targeted inhibition of specific cytokines (e.g., IL-6, IL-1β, TNF-α), regulators of NF-κB signaling, and modulation of inflammatory pathways can mitigate the catabolic effects of inflammation in IBD patients [20]. Anti-TNF-α therapy has emerged as a cornerstone intervention, demonstrating benefits for both tissues [55]. By mitigating the production and activity of pro-inflammatory cytokines, anti-TNF-α drugs not only alleviate gastrointestinal manifestations but also effectively reduce secondary complications of IBD, such as osteosarcopenia. The landmark study by DeBoer et al. [291] yielded compelling evidence for the beneficial effects of anti-TNF-α therapy, demonstrating significant enhancements in both BMD and muscle mass in IBD patients. According to Frei et al. [292], timely initiation of anti-TNF-α therapy in CD patients significantly reduces the incidence of osteoporosis. Treatment with anti-TNF-α agents in pediatric CD patients enhanced bone density, improved markers of bone formation, promoted linear growth, and increased lumbar bone mass [293-296]. Notably, both adalimumab and IFX have demonstrated efficacy in inducing long-term remission in a significant proportion of IBD patients, thereby mitigating bone loss and supporting overall musculoskeletal health [295,297-299]. Treatment with IFX in pediatric CD patients has been linked to a lower incidence of vitamin K deficiency [94]. This suggests that anti-TNF-α therapies may have a beneficial effect on vitamin K status by reducing systemic inflammation, enhancing intestinal absorption, and improving overall nutritional status. This potential benefit highlights the importance of considering the nutritional implications of anti-TNF-α treatment in managing pediatric CD. Shifting the focus to muscle health, a prospective study found significant gains in muscle health after anti-TNF-α treatment in active CD patients: increased quadriceps strength (after 25 weeks of IFX), greater muscle volume gains in males than females, reduced inflammation (lower serum inflammatory markers) and enhanced muscle growth (increased myogenin synthesis) [300]. Treatment with IFX or adalimumab for 3 months significantly improved BMI and muscle parameters, highlighting the beneficial effects of anti-TNF-α therapy on nutritional status and body composition in IBD patients [301].
However, the efficacy of anti-TNF-α treatment varies across different patient populations. This therapy may not reduce the risk of new vertebral fractures in IBD patients with previous fractures [302]. Studies have revealed that CD adolescents may experience bone and muscle impairments for up to 1 year following anti-TNF-α treatment, despite its therapeutic benefits [294]. A recent study revealed the association between IFX use and increased osteoporosis risk in PIBD patients, particularly those with low BMI, severe disease, poor nutritional status, low calcium levels and concurrent GCs use [303]. This finding emphasizes the need for personalized treatment approaches, careful monitoring, and management of potential risk factors to optimize musculoskeletal outcomes in IBD patients. Given the small sample size in this study, larger, well-controlled trials are needed to further investigate this relationship and identify potential risk factors or subgroups more vulnerable to adverse effects on bone health [303]. Singh et al.’s meta-analysis [304] showed that obesity is linked to poor response to anti-TNF-α therapies in IBD. Conversely, Bryant et al. [8] found no association between obesity markers and IBD phenotype, inflammation, or medication response. Anti-TNF-α therapy in pediatric CD patients demonstrated significant improvements during the first 6 months, marked by increases in fat-free mass and physical activity [69]. However, UC patients showed no significant changes in body composition [69].
The precise mechanisms underlying the impact of anti-TNF-α therapy on osteosarcopenia in IBD patients are complex and multifaceted, involving direct effects on bone and muscle metabolism and indirect effects through reduced intestinal and systemic inflammation [305].
Combination therapy demonstrates efficacy in addressing concurrent bone and muscle loss in IBD patients. The rationale behind combination therapy is its capacity to target multiple pathways involved in both bone and muscle deterioration. The growing interest in combinatorial approaches ranges from integrating anti-inflammatory agents with bone-specific treatments. A well-established combination therapy that has shown significant improvements in lumbar spine BMD in IBD patients is the combination of anti-TNF-α agents and an immunosuppressant, azathioprine [185]. Azathioprine benefits by reducing overall inflammation and enhancing nutrient absorption in IBD patients, which indirectly benefits bone health [185].
7. Bisphosphonate Therapy
Bisphosphonates, anti-catabolic agents used in high-risk fracture patients, may be considered in injectable form for those with moderate-to-high fracture risk [146,155,156]. Bisphosphonates block the osteoclastic activity with a consequent increase in bone density [306]. Several bisphosphonates have proven effective in increasing BMD in IBD patients, including alendronate, risedronate, pamidronate, etidronate, and ibandronate [307-310]. In a prospective randomized study, the effect of risedronate was evaluated on bone mass and vertebral fractures in osteoporotic postmenopausal women with IBD in remission for 1 year. After 1 year, BMD at lumbar spine trochanter and femoral neck was significantly higher in the risedronate group in comparison with baseline. Furthermore, both the incidence of vertebral fractures and the risk of developing new vertebral fractures decreased significantly [311].
Use of bisphosphonates is believed to be beneficial for spine and hip BMD [257,307]. However, the latest meta-analysis showed that different bisphosphonates increase BMD at the lumbar spine, but not at the hip site [312]. By reducing bone turnover, bisphosphonates may also lower inflammatory markers, contributing to musculoskeletal health in IBD [312]. However, longterm bisphosphonate use carries potential risks, including osteonecrosis of the jaw, atypical femoral fractures, gastrointestinal issues, and over-suppression of bone turnover. Regular monitoring is essential, particularly in young adult patients [312-315]. The variability in patient responses to bisphosphonate treatment highlights the need for personalized approaches in IBD management. Large-scale, long-term studies are essential to better understand the efficacy and safety of bisphosphonates in young adults with IBD. The combination of bisphosphonates with other treatments shows promise in IBD management. Combining bisphosphonates with anti-TNF-α therapy enhances BMD and potentially reduces fracture risk [316]. Studies demonstrate that combining risedronate, with calcium and vitamin D supplementation results in significantly greater improvements in BMD at the femoral trochanter and total hip in CD patients compared to using bisphosphonates alone [311,317]. This combination therapy effectively addresses both common nutrient deficiencies in IBD patients and the accelerated bone resorption. Additionally, the combination of vitamin D with ibandronate is cost-effective for preventing fractures in osteoporotic IBD patients [318,319]. Together, these synergistic effects ensure the availability of essential minerals for bone formation while simultaneously inhibiting bone resorption. A well-established approach for managing bone loss in IBD patients involves the use of intravenous pamidronate in combination with calcium and vitamin D supplementation [308]. Pamidronate inhibits osteoclast-mediated bone resorption, reduce bone turnover, and increase BMD. This combination therapy significantly improved BMD in IBD patients, particularly in critical areas, such as hip and lumbar spine [310]. This approach is particularly effective for patients who have not responded adequately to calcium and vitamin D supplementation alone. Moreover, intravenous pamidronate is advantageous for IBD patients with gastrointestinal complications, as it bypasses issues associated with oral medication absorption [312]. This combination therapy shows promise for quickly improving BMD; however, long-term safety data are limited. Further research is needed to determine the optimal frequency and duration of pamidronate treatment in IBD patients. Bisphosphonate therapy may not be suitable for patients with renal impairment. Careful patient selection and ongoing monitoring are essential to maximize the benefits while minimizing potential risks.
8. Hormonal Therapy
Obtaining sufficient vitamin D through diet can be difficult due to food sensitivities and gastrointestinal intolerance for IBD patients. As a result, oral supplementation often becomes the primary method for vitamin D replacement [320]. High-dose 1,25 dihydroxyvitamin D (1,25(OH)2 D) therapy reduces inflammation (IL-17A and interferon-γ) and the risk of relapse in CD, while not altering the risk for UC significantly [321-323]. A retrospective study has shown that high vitamin D levels before starting an anti-TNF-α therapy in IBD patients had a long-lasting response than patients with low vitamin D levels [324]. Research demonstrates that vitamin D supplementation enhances beneficial gut bacteria populations (Bacteroides and Parabacteroides) in a dose-dependent manner, potentially reducing IBD relapse risk [325].
Beyond gut health, vitamin D regulates calcium absorption and RANK/RANKL/OPG system [326]. Consistently, supplementation with calcium and vitamin D improved BMD at the lumbar spine and hip in CD patients [327]. Meta-analyses indicate a small benefit of vitamin D on BMD and a reduction in fractures among postmenopausal women with IBD [257]. In young IBD patients (ages 5–21), vitamin D supplementation has shown potential in reversing skeletal damage [207]. Early intervention with calcium and vitamin D supplementation is crucial for high-risk groups, including postmenopausal women, malnourished individuals, and those on GC therapy [160]. It is widely accepted that vitamin D supplementation should be provided during GC treatment to prevent bone damage in IBD patients [328].
Genetic factors play a crucial role in vitamin D metabolism and bone health. The VDR gene and its variants are particularly significant [80]. For instance, studies have shown that the TT genotype of VDR gene correlates with higher femoral neck bone mass specifically in UC patients [329,330]. However, further research is needed to fully understand the mechanisms behind this association.
Notably, studies have established positive correlations between vitamin D metabolism and muscle performance [60,89]. A daily 2000 IU vitamin D3 supplement improves muscle strength and trabecular BMD in PIBD patients [331]. Inflammatory CRP and disease parameters (CD and UC activity index scores) were similar between baseline and follow-up visits, concluding that vitamin D regimen was safe. Evidence suggests that maintaining normal vitamin D levels combined with regular exercise can prevent muscle mass reduction in CD. Additionally, vitamin D supplementation enhances hip muscle strength and reduces fall risk [332].
Some studies do not find a correlation between vitamin D levels and low BMD in IBD patients, suggesting outcomes may vary based on individual factors [78,185,333-335]. It is important to note that calcium and vitamin D supplementation may not significantly improve BMD in PIBD patients if pre-intervention nutritional intake was already adequate [267,268]. This highlights the importance of assessing baseline nutritional status before prescribing supplements for PIBD-related osteoporosis. A study explored the impact of vitamin D2 (monthly basis for 6 months of calcium supplementation for 12 months) on BMD in IBD patients [268]. Pediatric CD in the intervention group suffered skeletal maturation delay and higher disease activity than control group. However, the serum vitamin D of subjects receiving calcium alone and those receiving calcium and vitamin D supplementation together increased [268]. In PIBD, it was shown that patients with areal BMD at lumbar spine had higher (but not significant) total vitamin D intake than those with a normal lumbar spine areal BMD. This discrepancy in results may be attributed to impaired vitamin D absorption [228]. Furthermore, more research is needed on vitamin D supplementation in adult IBD populations to fill existing knowledge gaps.
9. Hormone Replacement Therapy
Hormone replacement therapy has been shown to improve disease activity in postmenopausal IBD women [336]. Interestingly, Khalili et al. [337] reported that while postmenopausal hormone therapy is associated with an increased risk of UC, it does not raise the risk of CD. This finding provides new insights into the potential role of estrogens in UC development.
Hormone replacement therapy effectively treats osteoporosis in IBD patients [338]. Teriparatide (recombinant human parathyroid hormone 1-34) is an anabolic agent that stimulates bone formation, increases the activity and lifespan of osteoblasts, enhances calcium absorption and renal tubular calcium reabsorption [339,340]. Androgen stimulates osteoblast precursors, inhibits osteoclast survival and development, and promotes muscle hypertrophy [341]. Selective androgen receptor modulators are emerging as promising treatments for improving muscle and bone health, offering potentially fewer androgenic side effects compared to conventional testosterone replacement therapy [342]. Estrogens enhance BMD through activation of the Wnt/β-catenin pathway, while improving muscle strength by reducing inflammatory cytokine production [343]. Studies have shown that oral estrogen not only prevent bone loss but also increases BMD over 2 years in postmenopausal IBD women [338].
Clinical trials in postmenopausal osteoporosis have demonstrated IGF-1 therapy’s efficacy in fracture prevention [55]. This treatment requires vigilant monitoring for potential side effects, particularly alterations in glucose metabolism and tissue growth promotion. Similarly, hormone replacement therapy effectively protects bone health but poses significant longterm risks, including breast cancer, cardiovascular complications, and thromboembolic events [75].
10. Treatment Considerations
Treatment of IBD-associated osteosarcopenia requires careful individualization based on several key factors. Clinicians must consider the specific IBD subtype, as CD and UC patients may respond differently to interventions. Disease activity plays a crucial role in treatment selection, as active inflammation may necessitate more aggressive therapy or modification of existing protocols. The specific characteristics of osteosarcopenia presentation, including the severity of bone loss and muscle deterioration, help guide therapeutic choices. Age and hormonal status significantly influence treatment decisions, particularly in pediatric patients and postmenopausal women who may require specialized approaches.
Successful management demands rigorous monitoring protocols. Regular assessment of both bone and muscle parameters is essential to track treatment effectiveness and adjust interventions as needed. Clinicians must carefully evaluate potential drug interactions, particularly given the complex medication regimens often required for IBD management. Long-term safety surveillance is crucial, especially for treatments like bisphosphonates and hormone replacement therapy that may carry risks with extended use. Treatment response should be monitored comprehensively, assessing improvements in both bone and muscle tissues to ensure the effectiveness of the integrated therapeutic approach. This systematic monitoring allows for timely adjustments to treatment strategies and helps optimize outcomes for patients with IBD-associated osteosarcopenia.
IBD-associated osteosarcopenia requires a multifaceted approach to understanding and management. Key elements include regular monitoring of inflammatory markers, bone density, muscle mass, and nutritional status. Early inflammation control is crucial to prevent bone and muscle impairment [344]. Comprehensive management requires optimizing nutritional intake and vitamin D supplementation, promoting physical activity, minimized GC exposure and developing tailored interventions [345]. Fostering collaboration among gastroenterologists, rheumatologists, endocrinologists, physical therapists, and researchers will advance understanding and management of musculoskeletal health in IBD patients.
Management challenges arise from delayed IBD diagnosis due to non-specific symptoms [346,347], heterogeneous disease presentations, unpredictable course of IBD, characterized by alternating periods of active inflammation and remission [216,252] and varying diagnostic criteria for sarcopenia across populations.
The path forward in managing IBD-associated osteosarcopenia requires several essential components working in concert. Integration of bone and muscle health assessments into routine IBD care forms the foundation, allowing for comprehensive monitoring of musculoskeletal health alongside gastrointestinal symptoms. This must be coupled with personalized approaches that consider each patient’s unique inflammatory profile and disease severity, enabling targeted interventions. Treatment strategies should combine multiple therapeutic pathways, recognizing the complex interplay between inflammation, bone metabolism, and muscle health. Early intervention and consistent monitoring are crucial for optimal outcomes. This comprehensive approach, emphasizing early recognition and personalized intervention, offers the best opportunity for improving outcomes in IBD-associated osteosarcopenia.
Recent advances in understanding the pathophysiology of IBD-associated osteosarcopenia have opened new avenues for therapeutic strategies. IL-12/23 inhibitors, particularly ustekinumab, have emerged as effective treatments for moderate-to-severe IBD [348,349]. By targeting the IL-12/23 pathway, these agents not only reduce gastrointestinal inflammation but also potentially decrease systemic inflammation contributing to bone loss. However, long-term studies specifically examining their effects on bone health in IBD patients are needed.
Several promising bone-targeted therapies are under investigation. Wnt/β-catenin pathway modulators, Bone morphogenetic protein (BMP-2)-2 analogs, and anti-IL-6 therapies show potential for enhancing bone formation. Strategic combinations of anabolic and antiresorptive agents have demonstrated efficacy in severe osteoporosis management. Clinical trials have shown that sequential therapy, starting with anabolic agents (teriparatide, romosozumab) followed by antiresorptives (denosumab, bisphosphonates), effectively maintains and enhances BMD [350-352]. The combination of denosumab, which inhibits osteoclast function through RANKL targeting [339,340,350,351], with teriparatide has shown superior BMD improvements compared to monotherapy, particularly in postmenopausal women. Similarly, combining romosozumab with denosumab enhances bone formation while preventing bone loss [56]. These approaches could be particularly valuable for IBD patients who experience rapid bone loss during disease flares, though specific studies in IBD populations are needed.
For muscle health, emerging therapies target key molecular pathways. Myostatin inhibitors have demonstrated promise in pre-clinical studies for increasing muscle mass and potentially improving bone density [352]. Recent research has identified BMP ligands as regulators of muscle mass, offering opportunities to target this specific branch of the TGF-β pathway [15]. Novel molecular targets include Irisin, which is released during exercise and exerts osteoprotective effects through Wnt/β-catenin, p38 MAPK, and extracellular signal-regulated kinase (ERK) signaling while suppressing osteoclast formation via RANKL/NFATc1 pathway interference [33,353]. Advanced drug delivery systems, including nanoparticle-based technologies, are being developed to enhance treatment efficacy and reduce side effects [354,355].
Future directions should focus on developing standardized, IBD-specific diagnostic criteria for osteosarcopenia, conducting longitudinal studies to evaluate long-term outcomes, investigating combination therapies targeting both bone and muscle, exploring personalized medicine approaches based on individual risk factors, establishing optimal exercise and nutritional intervention protocols, identifying reliable biomarkers for early detection and enhancing understanding of gut-bone and gut-muscle axes [13].
These comprehensive approaches, combined with targeted research, will improve our ability to prevent and treat musculoskeletal complications in IBD patients, ultimately enhancing their functional capacity and quality of life.

Funding Source

The authors received no financial support for the research, authorship, and/or publication of this article.

Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Data Availability Statement

Not applicable.

Author Contributions

Writing and approval of the final manuscript: Sharma S.

Fig. 1.
Proposed pathophysiological mechanisms of IBD-associated osteosarcopenia. The diagram illustrates the interrelationships between inflammatory, nutritional, and endocrine factors contributing to both bone and muscle loss in IBD. Elevated pro-inflammatory cytokines activate pathways that disrupt bone homeostasis (via RANK/RANKL dysregulation) and muscle metabolism (via increased protein breakdown and mitochondrial dysfunction). These processes are further influenced by nutritional deficiencies and endocrine abnormalities, collectively resulting in IBD-associated osteosarcopenia. TNF, tumor necrosis factor; IL, interleukin; IFN, interferon; IGF, insulin-like growth factor; RANKL, receptor activator of nuclear factor kappa-β (RANK) ligand; IBD, inflammatory bowel disease.
ir-2024-00185f1.jpg
Fig. 2.
(A) Schematic diagram illustrating RANKL-mediated bone loss in IBD. The inflamed gut in IBD shows increased presence of Th17 and Th1 cells, producing pro-inflammatory cytokines (IFN-γ, IL-6, TNF-α). Th17 cells migrate to and accumulate in the bone marrow and express RANKL and TNF-α, directly promoting osteoclast differentiation. Also, Th17 cells produce IL-17 and IL-22, stimulating local inf lammation and activating osteoblasts. Osteoblasts increase RANKL production, produce chemokines (MCP-1 and MIP-1α), which attract monocytes from the blood into the bone marrow. Osteoclasts are activated by RANKL binding to RANK receptors, resulting in increased bone resorption. Osteoblasts also produce OPG, which normally inhibits RANKL. However, in IBD, the balance is shifted towards increased RANKL activity. (B) Integrated signaling pathways in IBD-induced muscle wasting. This schematic diagram depicts the molecular mechanisms by which inflammatory cytokines (TNF-α, IL-6, IL-1β) promote muscle wasting through multiple pathways within muscle cells (represented by the yellow oval). The pathways include (1) decreased IGF-1 signaling leading to reduced PI3K/AKT/mTOR activity and enhanced FOXO signaling, resulting in decreased muscle protein synthesis; (2) increased myostatin expression activating Smad2/3/Smad4 signaling; and (3) NF-κB and MAPK activation. All these pathways converge to upregulate ubiquitin E3 ligases (Atrogin-1, MURF-1), leading to enhanced muscle protein degradation. Red downward arrows indicate decreased activity, while blue upward arrows indicate increased activity. This comprehensive pathway is particularly relevant in IBD patients receiving glucocorticoid therapy, as it illustrates how their treatment may potentially contribute to muscle wasting alongside inflammatory mediators. RANKL, receptor activator of nuclear factor kappa-β (RANK) ligand; IBD, inflammatory bowel disease; IFN, interferon; IL, interleukin; TNF, tumor necrosis factor; MCP-1, monocyte chemoattractant protein-1; MIP-1α, macrophage inflammatory protein-1α; OPG, osteoprotegerin; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; mTOR, mechanistic target of rapamycin; FOXO, forkhead box O; NF-κB, nuclear transcription factor-kappa B; MAPK, mitogen-activated protein kinase.
ir-2024-00185f2.jpg
Fig. 3.
Diagnostic and monitoring algorithm for inflammatory bowel disease (IBD)-associated osteosarcopenia. The flowchart illustrates the systematic approach to screening, assessment, and monitoring of osteosarcopenia in newly diagnosed IBD patients. Following initial IBD diagnosis, patients undergo risk stratification to determine the timing of screening (immediate vs. within 6 months). A complete assessment package includes 3 core components: dual-energy X-ray absorptiometry (DXA) scan for bone health evaluation, muscle mass and function testing, and comprehensive risk factor review. Based on the results analysis, patients are directed to either regular monitoring (with annual or biennial reviews) or intervention pathways requiring specialist referral. This protocol ensures standardized evaluation and appropriate follow-up based on individual patient risk profiles and assessment outcomes.
ir-2024-00185f3.jpg
Fig. 4.
Comprehensive assessment framework for bone and muscle health in IBD-associated osteosarcopenia. The diagram illustrates 2 major assessment domains: bone health (upper panel) and muscle health (lower panel). Bone health evaluation encompasses regular BMD monitoring through imaging techniques, bone microarchitecture analysis via trabecular bone scoring, and bone turnover markers for both resorption (CTX, NTX, P1NP) and formation (OC, ALP). Muscle health assessment includes imaging-based muscle mass quantification, functional testing of physical performance, and relevant biomarkers categorized as nutritional, inflammatory, and muscle-specific markers. IBD, inflammatory bowel disease; BMD, bone mineral density; DXA, dual-energy X-ray absorptiometry; CT, computed tomography; MRI, magnetic resonance imaging; CTX, C-terminal telopeptide of type I collagen; NTX, N-terminal telopeptide of type I collagen; P1NP; procollagen type 1 N propeptide; OC, osteocalcin; ALP, alkaline phosphatase; BIA, bioelectrical impedance analysis; CRP, C-reactive protein; IL, interleukin; TNF, tumor necrosis factor; IGF, insulin-like growth factor.
ir-2024-00185f4.jpg
Fig. 5.
Non-pharmacological interventions for inflammatory bowel disease (IBD)-associated osteosarcopenia. Main categories of nonpharmacological interventions for managing osteosarcopenia in IBD patients are (1) nutritional therapies, comprising nutritional supplements (including protein, vitamin D, calcium, and omega-3 fatty acids), exclusive enteral nutrition, and parenteral nutrition; (2) exercise interventions, including weight-bearing exercises for bone health, resistance training for muscle strength, and aerobic exercise for cardiovascular fitness; and (3) lifestyle modifications, focusing on stress management, smoking/tobacco cessation, and reduction of alcohol consumption. These interventions collectively address bone health, muscle strength, and overall well-being in IBD patients with osteosarcopenia.
ir-2024-00185f5.jpg
Fig. 6.
Pharmacological interventions for IBD-associated osteosarcopenia. Pharmacological interventions for IBD-associated osteosarcopenia. Major categories of pharmacological treatments for osteosarcopenia in IBD patients include: (1) TNF-α inhibitors, featuring IFX therapy (with anti-inflammatory and anabolic effects), immunomodulators like azathioprine, and combination therapy; (2) RANKL inhibitors, specifically bisphosphonate therapy with anti-catabolic properties; (3) sclerostin inhibitors, particularly romosozumab, which provides both anabolic and anti-catabolic effects; and (4) hormonal therapy options, including vitamin D supplementation, PTH hormoneteriparatide (anabolic), and sex hormones (testosterone and estrogen). IBD, inflammatory bowel disease; TNF, tumor necrosis factor; IFX, infliximab; RANKL, receptor activator of nuclear factor kappa-β ligand; PTH, parathyroid.
ir-2024-00185f6.jpg
Table 1.
Comparison between General Osteosarcopenia versus IBD-Associated Osteosarcopenia
Aspect General osteosarcopenia IBD-associated osteosarcopenia
Age of onset Typically occurs in older adults (> 65 yr) [13] Can occur at any age, including young adults and even children with IBD [14]
Primary cause Age-related decline in bone and muscle mass [15] Chronic inflammation, malnutrition, and treatment side effects [16]
Progression Usually gradual, over many years [17] Can be more rapid, especially during disease flares [18]
Inflammation Low-grade chronic inflammation associated with aging [19] High-grade, disease-specific inflammation [20]
Nutritional factors General malnutrition, often due to decreased intake [21] Malnutrition due to decreased intake, malabsorption, and increased nutrient losses [22]
Physical activity Often decreased due to age-related factors [23] May be decreased due to disease symptoms, fatigue, and complications [24]
Diagnostic challenges Relatively straightforward, based on established criteria [25] May be complicated by IBD-related factors (e.g., altered body composition, disease activity) [7]
Treatment approach General strategies applicable to most patients [26] Needs to be tailored to IBD-specific factors and potential treatment interactions [18]
Reversibility Limited reversibility, focus often on slowing progression [27] Potentially more reversible with successful IBD treatment and remission [28]
Impact on quality of life Gradual impact on mobility and independence [29] Can have sudden, significant impacts during disease flares [30]
Associated risks Primarily fractures and loss of independence [31] Increased surgical risks, complications of IBD treatments, and disease progression [32]

IBD, inflammatory bowel disease.

Table 2.
Overview of Osteosarcopenia Characteristics across Age Groups and Sex Differences
Category Bone health Muscle health Risk factors & clinical features
Pediatric population (< 18 yr) • 41.4%–46.7% low BMD [126] • Significantly lower muscle mass [180] • Daily GC therapy [126]
• Early onset of bone changes • Muscle changes predict disease severity • Vitamin D/calcium deficiency
• Disease progression impacts bone metabolism • Early sarcopenia development • Hypogonadism
• Chronic inflammation
• Growth impairment
Young adults (18–50 yr) • Osteoporosis: 2.3% in < 50 yr [181] • Sarcopenia: 56.8% overall [184] • Disease duration [185]
• Osteopenia: UC 20.1%, CD 17.2% [182] • CD: 57.5% prevalence [184] • Active disease state [84]
• More pronounced in < 30 yr diagnosis [183] • UC: 53.2% prevalence [184] • Malnutrition: 60.1% [186]
• High prevalence (12%–51%) in early 30s • Surgery requirements [187]
• Treatment response
Older adults (> 50 yr) • Osteoporosis: 18.2% [181] • Higher sarcopenia rates [188] • High frailty index [181]
• Higher prevalence in CD: 7%–15% [173] • Increased disability risk [189] • Long-term GC use
• UC: 2%–9% osteoporosis rate [173] • Complex with age-related decline • Comorbidities
• Cumulative disease burden [190]
Sex-specific patterns • Males: Higher risk in CD [191] • Males: Higher sarcopenia risk [184] • Male sex: risk factor in both conditions [84]
• Males: Low BMI impact [191] • Males:(SMI<49–52.4cm²/m²) [187,192] • Treatment response variations
• Females: Age-related risk increase [184] • Females: (SMI < 31–38.5 cm²/m²) [187,192] • Different assessment thresholds
• Sex-specific cutoff values • Sex-specific monitoring needed
Disease-specific features • CD: Higher osteoporosis rates [173] • CD: Poorer nutritional status [186] • Disease location impact [84]
• UC: Better bone outcomes [173] • UC: Better muscle preservation [186] • Treatment strategies [185]
• Site-specific variations [190] • Disease activity correlation [189] • Surgical history [191]
• Hospital admissions [190]
• Anti-TNF-α/AZA therapy response [185]

BMD, bone mineral density; GC, glucocorticoid; UC, ulcerative colitis; CD, Crohn's disease; BMI, body mass index; SMI, skeletal muscle index; TNF, tumor necrosis factor; AZA, azathioprine.

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      Gut, bone, and muscle: the triad of osteosarcopenia in inflammatory bowel disease
      Image Image Image Image Image Image
      Fig. 1. Proposed pathophysiological mechanisms of IBD-associated osteosarcopenia. The diagram illustrates the interrelationships between inflammatory, nutritional, and endocrine factors contributing to both bone and muscle loss in IBD. Elevated pro-inflammatory cytokines activate pathways that disrupt bone homeostasis (via RANK/RANKL dysregulation) and muscle metabolism (via increased protein breakdown and mitochondrial dysfunction). These processes are further influenced by nutritional deficiencies and endocrine abnormalities, collectively resulting in IBD-associated osteosarcopenia. TNF, tumor necrosis factor; IL, interleukin; IFN, interferon; IGF, insulin-like growth factor; RANKL, receptor activator of nuclear factor kappa-β (RANK) ligand; IBD, inflammatory bowel disease.
      Fig. 2. (A) Schematic diagram illustrating RANKL-mediated bone loss in IBD. The inflamed gut in IBD shows increased presence of Th17 and Th1 cells, producing pro-inflammatory cytokines (IFN-γ, IL-6, TNF-α). Th17 cells migrate to and accumulate in the bone marrow and express RANKL and TNF-α, directly promoting osteoclast differentiation. Also, Th17 cells produce IL-17 and IL-22, stimulating local inf lammation and activating osteoblasts. Osteoblasts increase RANKL production, produce chemokines (MCP-1 and MIP-1α), which attract monocytes from the blood into the bone marrow. Osteoclasts are activated by RANKL binding to RANK receptors, resulting in increased bone resorption. Osteoblasts also produce OPG, which normally inhibits RANKL. However, in IBD, the balance is shifted towards increased RANKL activity. (B) Integrated signaling pathways in IBD-induced muscle wasting. This schematic diagram depicts the molecular mechanisms by which inflammatory cytokines (TNF-α, IL-6, IL-1β) promote muscle wasting through multiple pathways within muscle cells (represented by the yellow oval). The pathways include (1) decreased IGF-1 signaling leading to reduced PI3K/AKT/mTOR activity and enhanced FOXO signaling, resulting in decreased muscle protein synthesis; (2) increased myostatin expression activating Smad2/3/Smad4 signaling; and (3) NF-κB and MAPK activation. All these pathways converge to upregulate ubiquitin E3 ligases (Atrogin-1, MURF-1), leading to enhanced muscle protein degradation. Red downward arrows indicate decreased activity, while blue upward arrows indicate increased activity. This comprehensive pathway is particularly relevant in IBD patients receiving glucocorticoid therapy, as it illustrates how their treatment may potentially contribute to muscle wasting alongside inflammatory mediators. RANKL, receptor activator of nuclear factor kappa-β (RANK) ligand; IBD, inflammatory bowel disease; IFN, interferon; IL, interleukin; TNF, tumor necrosis factor; MCP-1, monocyte chemoattractant protein-1; MIP-1α, macrophage inflammatory protein-1α; OPG, osteoprotegerin; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; mTOR, mechanistic target of rapamycin; FOXO, forkhead box O; NF-κB, nuclear transcription factor-kappa B; MAPK, mitogen-activated protein kinase.
      Fig. 3. Diagnostic and monitoring algorithm for inflammatory bowel disease (IBD)-associated osteosarcopenia. The flowchart illustrates the systematic approach to screening, assessment, and monitoring of osteosarcopenia in newly diagnosed IBD patients. Following initial IBD diagnosis, patients undergo risk stratification to determine the timing of screening (immediate vs. within 6 months). A complete assessment package includes 3 core components: dual-energy X-ray absorptiometry (DXA) scan for bone health evaluation, muscle mass and function testing, and comprehensive risk factor review. Based on the results analysis, patients are directed to either regular monitoring (with annual or biennial reviews) or intervention pathways requiring specialist referral. This protocol ensures standardized evaluation and appropriate follow-up based on individual patient risk profiles and assessment outcomes.
      Fig. 4. Comprehensive assessment framework for bone and muscle health in IBD-associated osteosarcopenia. The diagram illustrates 2 major assessment domains: bone health (upper panel) and muscle health (lower panel). Bone health evaluation encompasses regular BMD monitoring through imaging techniques, bone microarchitecture analysis via trabecular bone scoring, and bone turnover markers for both resorption (CTX, NTX, P1NP) and formation (OC, ALP). Muscle health assessment includes imaging-based muscle mass quantification, functional testing of physical performance, and relevant biomarkers categorized as nutritional, inflammatory, and muscle-specific markers. IBD, inflammatory bowel disease; BMD, bone mineral density; DXA, dual-energy X-ray absorptiometry; CT, computed tomography; MRI, magnetic resonance imaging; CTX, C-terminal telopeptide of type I collagen; NTX, N-terminal telopeptide of type I collagen; P1NP; procollagen type 1 N propeptide; OC, osteocalcin; ALP, alkaline phosphatase; BIA, bioelectrical impedance analysis; CRP, C-reactive protein; IL, interleukin; TNF, tumor necrosis factor; IGF, insulin-like growth factor.
      Fig. 5. Non-pharmacological interventions for inflammatory bowel disease (IBD)-associated osteosarcopenia. Main categories of nonpharmacological interventions for managing osteosarcopenia in IBD patients are (1) nutritional therapies, comprising nutritional supplements (including protein, vitamin D, calcium, and omega-3 fatty acids), exclusive enteral nutrition, and parenteral nutrition; (2) exercise interventions, including weight-bearing exercises for bone health, resistance training for muscle strength, and aerobic exercise for cardiovascular fitness; and (3) lifestyle modifications, focusing on stress management, smoking/tobacco cessation, and reduction of alcohol consumption. These interventions collectively address bone health, muscle strength, and overall well-being in IBD patients with osteosarcopenia.
      Fig. 6. Pharmacological interventions for IBD-associated osteosarcopenia. Pharmacological interventions for IBD-associated osteosarcopenia. Major categories of pharmacological treatments for osteosarcopenia in IBD patients include: (1) TNF-α inhibitors, featuring IFX therapy (with anti-inflammatory and anabolic effects), immunomodulators like azathioprine, and combination therapy; (2) RANKL inhibitors, specifically bisphosphonate therapy with anti-catabolic properties; (3) sclerostin inhibitors, particularly romosozumab, which provides both anabolic and anti-catabolic effects; and (4) hormonal therapy options, including vitamin D supplementation, PTH hormoneteriparatide (anabolic), and sex hormones (testosterone and estrogen). IBD, inflammatory bowel disease; TNF, tumor necrosis factor; IFX, infliximab; RANKL, receptor activator of nuclear factor kappa-β ligand; PTH, parathyroid.

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      Gut, bone, and muscle: the triad of osteosarcopenia in inflammatory bowel disease
      Aspect General osteosarcopenia IBD-associated osteosarcopenia
      Age of onset Typically occurs in older adults (> 65 yr) [13] Can occur at any age, including young adults and even children with IBD [14]
      Primary cause Age-related decline in bone and muscle mass [15] Chronic inflammation, malnutrition, and treatment side effects [16]
      Progression Usually gradual, over many years [17] Can be more rapid, especially during disease flares [18]
      Inflammation Low-grade chronic inflammation associated with aging [19] High-grade, disease-specific inflammation [20]
      Nutritional factors General malnutrition, often due to decreased intake [21] Malnutrition due to decreased intake, malabsorption, and increased nutrient losses [22]
      Physical activity Often decreased due to age-related factors [23] May be decreased due to disease symptoms, fatigue, and complications [24]
      Diagnostic challenges Relatively straightforward, based on established criteria [25] May be complicated by IBD-related factors (e.g., altered body composition, disease activity) [7]
      Treatment approach General strategies applicable to most patients [26] Needs to be tailored to IBD-specific factors and potential treatment interactions [18]
      Reversibility Limited reversibility, focus often on slowing progression [27] Potentially more reversible with successful IBD treatment and remission [28]
      Impact on quality of life Gradual impact on mobility and independence [29] Can have sudden, significant impacts during disease flares [30]
      Associated risks Primarily fractures and loss of independence [31] Increased surgical risks, complications of IBD treatments, and disease progression [32]
      Category Bone health Muscle health Risk factors & clinical features
      Pediatric population (< 18 yr) • 41.4%–46.7% low BMD [126] • Significantly lower muscle mass [180] • Daily GC therapy [126]
      • Early onset of bone changes • Muscle changes predict disease severity • Vitamin D/calcium deficiency
      • Disease progression impacts bone metabolism • Early sarcopenia development • Hypogonadism
      • Chronic inflammation
      • Growth impairment
      Young adults (18–50 yr) • Osteoporosis: 2.3% in < 50 yr [181] • Sarcopenia: 56.8% overall [184] • Disease duration [185]
      • Osteopenia: UC 20.1%, CD 17.2% [182] • CD: 57.5% prevalence [184] • Active disease state [84]
      • More pronounced in < 30 yr diagnosis [183] • UC: 53.2% prevalence [184] • Malnutrition: 60.1% [186]
      • High prevalence (12%–51%) in early 30s • Surgery requirements [187]
      • Treatment response
      Older adults (> 50 yr) • Osteoporosis: 18.2% [181] • Higher sarcopenia rates [188] • High frailty index [181]
      • Higher prevalence in CD: 7%–15% [173] • Increased disability risk [189] • Long-term GC use
      • UC: 2%–9% osteoporosis rate [173] • Complex with age-related decline • Comorbidities
      • Cumulative disease burden [190]
      Sex-specific patterns • Males: Higher risk in CD [191] • Males: Higher sarcopenia risk [184] • Male sex: risk factor in both conditions [84]
      • Males: Low BMI impact [191] • Males:(SMI<49–52.4cm²/m²) [187,192] • Treatment response variations
      • Females: Age-related risk increase [184] • Females: (SMI < 31–38.5 cm²/m²) [187,192] • Different assessment thresholds
      • Sex-specific cutoff values • Sex-specific monitoring needed
      Disease-specific features • CD: Higher osteoporosis rates [173] • CD: Poorer nutritional status [186] • Disease location impact [84]
      • UC: Better bone outcomes [173] • UC: Better muscle preservation [186] • Treatment strategies [185]
      • Site-specific variations [190] • Disease activity correlation [189] • Surgical history [191]
      • Hospital admissions [190]
      • Anti-TNF-α/AZA therapy response [185]
      Table 1. Comparison between General Osteosarcopenia versus IBD-Associated Osteosarcopenia

      IBD, inflammatory bowel disease.

      Table 2. Overview of Osteosarcopenia Characteristics across Age Groups and Sex Differences

      BMD, bone mineral density; GC, glucocorticoid; UC, ulcerative colitis; CD, Crohn's disease; BMI, body mass index; SMI, skeletal muscle index; TNF, tumor necrosis factor; AZA, azathioprine.

      Table 1.

      Table 2.

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