Search Results (266)

Background/Objectives: Cannabinoid use is rising among patients undergoing spinal fusion, yet its influence on bone healing is poorly defined. The endocannabinoid system (ECS)—through cannabinoid receptors 1 (CB1) and 2 (CB2)—modulates skeletal metabolism. We reviewed preclinical, mechanistic and clinical evidence to clarify how individual cannabinoids affect fracture repair and spinal arthrodesis. Methods: PubMed, Web of Science and Scopus were searched from inception to 31 May 2025 with the terms “cannabinoid”, “CB1”, “CB2”, “spinal fusion”, “fracture”, “osteoblast” and “osteoclast”. Animal studies, in vitro experiments and clinical reports that reported bone outcomes were eligible. Results: CB2 signaling was uniformly osteogenic. CB2-knockout mice developed high-turnover osteoporosis, whereas CB2 agonists (HU-308, JWH-133, HU-433, JWH-015) restored trabecular volume, enhanced osteoblast activity and strengthened fracture callus. Cannabidiol (CBD), a non-psychoactive phytocannabinoid with CB2 bias, accelerated early posterolateral fusion in rats and reduced the RANKL/OPG ratio without compromising final union. In contrast, sustained or high-dose Δ⁹-tetrahydrocannabinol (THC) activation of CB1 slowed chondrocyte hypertrophy, decreased mesenchymal-stromal-cell mineralization and correlated clinically with 6–10% lower bone-mineral density and a 1.8–3.6-fold higher pseudarthrosis or revision risk. Short-course or low-dose THC appeared skeletal neutral. Responses varied with sex, age and genetic background; no prospective trials defined safe perioperative dosing thresholds. Conclusions: CB2 activation and CBD consistently favor bone repair, whereas chronic high-THC exposure poses a modifiable risk for nonunion in spine surgery. Prospective, receptor-specific trials stratified by THC/CBD ratio, patient sex and ECS genotype are needed to establish evidence-based cannabinoid use in spinal fusion. Full article

Background: Inflammatory bowel diseases (IBD), such as Crohn’s disease (CD) and ulcerative colitis (UC), may impair bone metabolism, particularly in children. The RANKL/OPG axis, as a key regulator of bone turnover, may contribute to these disturbances. However, data in the pediatric population remain limited. Methods: A single-center, prospective observational study included 100 children aged 4–18 years, with a comparable number of girls and boys. Among them, 72 had IBD (27 CD, 45 UC) and 28 were healthy controls. Anthropometric, biochemical, and densitometric assessments were performed, including serum levels of RANKL and OPG, and markers of inflammation and bone turnover. Results: Children with CD had significantly lower height and weight percentiles compared to UC and controls. Serum RANKL and the RANKL/OPG ratio were significantly elevated in IBD patients, particularly in CD (p < 0.01). Total body BMD Z-scores were lower in IBD compared to controls (p = 0.03). Low BMD was found in 14.7% of UC and 26.3% of CD patients. In both groups, over 30% had values in the “gray zone” (−1.0 to −2.0). A positive correlation was observed between height and weight and bone density (p < 0.01). Higher OPG was associated with lower body weight (p < 0.001), while increased RANKL correlated with osteocalcin (p = 0.03). Patients receiving biological therapy had significantly lower BMD. Conclusions: Pediatric IBD is associated with significant alterations in the RANKL/OPG axis and reduced bone density. These findings support early screening and suggest RANKL/OPG as a potential biomarker of skeletal health. Full article

Bone metastasis remains a significant cause of morbidity and diminished quality of life in patients with advanced breast, prostate, and lung cancers. Emerging research highlights the pivotal role of reversible epigenetic alterations, including DNA methylation, histone modifications, chromatin remodeling complex dysregulation, and non-coding RNA networks, in orchestrating each phase of skeletal colonization. Site-specific promoter hypermethylation of tumor suppressor genes such as HIN-1 and RASSF1A, alongside global DNA hypomethylation that activates metastasis-associated genes, contributes to cancer cell plasticity and facilitates epithelial-to-mesenchymal transition (EMT). Key histone modifiers, including KLF5, EZH2, and the demethylases KDM4/6, regulate osteoclastogenic signaling pathways and the transition between metastatic dormancy and reactivation. Simultaneously, SWI/SNF chromatin remodelers such as BRG1 and BRM reconfigure enhancer–promoter interactions that promote bone tropism. Non-coding RNAs, including miRNAs, lncRNAs, and circRNAs (e.g., miR-34a, NORAD, circIKBKB), circulate via exosomes to modulate the RANKL/OPG axis, thereby conditioning the bone microenvironment and fostering the formation of a pre-metastatic niche. These mechanistic insights have accelerated the development of epigenetic therapies. DNA methyltransferase inhibitors (e.g., decitabine, guadecitabine) have shown promise in attenuating osteoclast differentiation, while histone deacetylase inhibitors display context-dependent effects on tumor progression and bone remodeling. Inhibitors targeting EZH2, BET proteins, and KDM1A are now advancing through early-phase clinical trials, often in combination with bisphosphonates or immune checkpoint inhibitors. Moreover, novel approaches such as CRISPR/dCas9-based epigenome editing and RNA-targeted therapies offer locus-specific reprogramming potential. Together, these advances position epigenetic modulation as a promising axis in precision oncology aimed at interrupting the pathological crosstalk between tumor cells and the bone microenvironment. This review synthesizes current mechanistic understanding, evaluates the therapeutic landscape, and outlines the translational challenges ahead in leveraging epigenetic science to prevent and treat bone metastases. Full article

Osteoclastogenesis—the activation and differentiation of osteoclasts—is one of the pivotal processes of bone remodeling and is regulated by RANKL/RANK signaling, the decoy function of osteoprotegerin (OPG), and a cascade of pro- and anti-inflammatory cytokines. The disruption of this balance leads to pathological bone loss in diseases such as osteoporosis and rheumatoid arthritis. FFAR4 (Free Fatty Acid Receptor 4), a G protein-coupled receptor for long-chain omega-3 fatty acids, has been confirmed as a key mediator of metabolic and anti-inflammatory effects. This review focuses on how FFAR4 acts as the selective receptor for the omega-3 fatty acid docosahexaenoic acid (DHA). It activates two divergent signaling pathways. The Gαq-dependent cascade facilitates intracellular calcium mobilization and ERK1/2 activation. Meanwhile, β-arrestin-2 recruitment inhibits NF-κB. These collective actions reshape the cytokine environment. In macrophages, DHA–FFAR4 signaling lowers the levels of TNF-α, interleukin-6 (IL-6), and IL-1β while increasing IL-10 secretion. Consequently, the activation of NFATc1 and NF-κB p65 is profoundly suppressed under TNF-α or RANKL stimulation. Additionally, DHA modulates the RANKL/OPG axis in osteoblastic cells by suppressing RANKL expression, thereby reducing osteoclast differentiation in an inflammatory mouse model. Full article

Tea is one of the most consumed beverages in the world, belonging to the category of compounds known as tannins and flavonoids. One of the polyphenols found in large amounts in green tea leaves (Camellia sinensis) is epigallocatechin-3-O-gallate (EGCG). Though EGCG has shown some pharmacological effects, to date, it has not been utilised as a therapeutic agent. This is attributed to the fact that EGCG lacks adequate stability, and it is known to degrade through epimerization or auto-oxidation processes, especially when it is exposed to light, temperature fluctuations, some pH values, or the presence of oxygen. Consuming green tea with EGCG can alleviate the effects of bone diseases, such as osteoporosis, and support faster bone regeneration in the case of fractures. Therefore, this review focuses on the current state of research, highlighting the effects of EGCG on bone biology, such as enhancing osteoblast differentiation, promoting bone mineralisation, improving bone microarchitecture, and inhibiting osteoclastogenesis through the modulation of the RANK/RANKL/OPG pathway. Additionally, EGCG exerts antioxidant, anti-inflammatory, and dose-dependent effects on bone cells. It also downregulates inflammatory markers (TNF-α, IL-1β, and COX-2) and reduces oxidative stress via the inhibition of reactive oxygen species generation and the activation of protective signalling pathways (e.g., MAPK and NF-κB). Studies in animal models confirm that EGCG supplementation leads to increased bone mass and strength. These findings collectively support the further exploration of EGCG as an adjunct in the treatment and prevention of metabolic bone diseases. The authors aim to present the relationship between EGCG and bone health, highlighting issues for future research and clinical applications. Full article

Background: The biological mediators for the epidemiologic overlap between osteoporosis and dementia are unclear. We undertook a scoping review of clinical studies to identify genetic and biological factors linked with these degenerative conditions, exploring the mechanisms and pathways connecting both conditions. Methods: Studies selected (1) involved clinical research investigating genetic factors or biomarkers associated with dementia or osteoporosis, and (2) were published in English in a peer-reviewed journal between July 1993 and March 2025. We searched Medline Ovid, Embase, PsycINFO, the Cochrane Library, the Web of Science databases, Google Scholar, and the reference lists of studies following the guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR). Results: Twenty-three studies were included in this review. These explored the role of the APOE polymorphism (n = 2) and the APOE4 allele (n = 13), associations between TREM2 mutation and late onset AD (n = 1), and associations between amyloid beta and bone remodeling (n = 1); bone-related biomarkers like DKK1, OPG, and TRAIL as predictors of cognitive change (n = 2); extracellular vesicles as bone–brain communication pathways (1); and the role of dementia-related genes (n = 1), AD-related CSF biomarkers (n = 1), and parathyroid hormone (PTH) (n = 1) in osteoporosis–dementia pathophysiology. Conclusions: Bone-related biomarkers active in the Wnt/β-Catenin pathway (Dkk1 and sclerostin) and the RANKL/RANK/OPG pathway (OPG/TRAIL ratio) present consistent evidence of involvement in AD and osteoporosis development. Reports proposing APOE4 as a causal genetic link for both osteoporosis and AD in women are not corroborated by newer observational studies. The role of Aβ toxicity in osteoporosis development is unverified in a large clinical study. Full article

Introduction: Celiac disease (CD) impairs bone development in children through inflammation and nutrient malabsorption. Osteoprotegerin (OPG), a decoy receptor for RANKL, plays a role in bone remodeling and is increasingly recognized as a potential biomarker of bone metabolism and inflammation. However, its clinical significance in pediatric CD remains unclear. Aim: To evaluate the relationship between OPG levels, growth parameters, and delayed bone age in children with CD, and to assess OPG’s potential as a biomarker of bone health and disease activity. Methods: This three-year case–control study included 146 children: 25 with newly diagnosed CD (Group A), 54 with established CD on a gluten-free diet (Group B), and 67 healthy controls (Group C). Participants underwent clinical, anthropometric, and laboratory assessments at baseline and after 6 months (Groups A and B). OPG and osteocalcin were measured, and bone age was assessed radiologically. Statistical analyses included ANOVA, Spearman’s correlations, and binomial logistic regression. Results: OPG levels were highest in newly diagnosed children (Group A), showing a non-significant decrease after gluten-free diet initiation. OPG correlated negatively with age and height in CD patients and controls, and positively with hemoglobin and iron in Group B. Logistic regression revealed no significant predictive value of OPG for delayed bone age, although a trend was observed in Group B (p = 0.091). Children in long-term remission exhibited bone maturation patterns similar to healthy peers. Conclusions: OPG levels reflect disease activity and growth delay in pediatric CD but lack predictive power for delayed bone age. While OPG may serve as a secondary marker of bone turnover and inflammatory status, it is not suitable as a standalone biomarker for skeletal maturation. These findings highlight the need for integrative biomarker panels to guide bone health monitoring in children with CD. Full article

Tanshinones are a class of lipophilic diterpenoid quinones extracted from Salvia miltiorrhiza (Dan shen), a widely used herb in traditional Chinese medicine. These compounds, particularly tanshinone IIA (T-IIA) and sodium tanshinone sulfonate (STS), have been acknowledged for their broad spectrum of biological activities, including anti-inflammatory, antioxidant, anti-tumor, antiresorptive, and antimicrobial effects. Recent studies have highlighted the potential of tanshinones in the treatment of osteolytic diseases, characterized by excessive bone resorption, such as osteoporosis, rheumatoid arthritis, and periodontitis. The therapeutic effects of tanshinones in these diseases are primarily attributed to their ability to inhibit osteoclast differentiation and activity, suppress inflammatory cytokine production (e.g., tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6), and modulate critical signaling pathways, including NF-kB, MAPK, PI3K/Akt, and the RANKL/RANK/OPG axis. Additionally, tanshinones promote osteoblast differentiation and mineralization by enhancing the expression of osteogenic markers such as Runx2, ALP, and OCN. Preclinical models have demonstrated that T-IIA and STS can significantly reduce bone destruction and inflammatory cell infiltration in arthritic joints and periodontal tissues while also enhancing bone microarchitecture in osteoporotic conditions. This review aims to provide a comprehensive overview of the pharmacological actions of tanshinones in osteolytic diseases, summarizing current experimental findings, elucidating underlying molecular mechanisms, and discussing the challenges and future directions for their clinical application as novel therapeutic agents in bone-related disorders, especially periodontitis. Despite promising in vitro and in vivo findings, clinical evidence remains limited, and further investigations are necessary to validate the efficacy, safety, and pharmacokinetics of tanshinones in human populations. Full article

Periodontitis is an inflammatory disease that affects the periodontal supporting tissues. Its cardinal clinical manifestations encompass gingival inflammation, periodontal pocket formation, and alveolar bone resorption. Urolithin A (UA), a gut microbiota-derived metabolite of ellagitannins, is known for its anti-inflammatory and osseous-protective properties. Nonetheless, the impact of UA on periodontitis remains unknown. To investigate the preventive effect of UA, we employed a lipopolysaccharide (LPS)-induced inflammation model in RAW 264.7 mouse macrophages, a receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation model, and a ligature-induced periodontitis model in mice. The expression of inflammatory factors (tumor necrosis factor-α, TNF-α; interleukin-6, IL-6) was analyzed to assess anti-inflammatory efficacy. Bone loss in mice with periodontitis was assessed through histological and imaging techniques, including haematoxylin and eosin staining to evaluate alveolar bone morphology, Masson’s trichrome staining to visualize collagen fiber distribution, and micro-computed tomography scanning to quantify bone structural parameters. Additionally, we investigated the underlying mechanisms by examining osteoclast activity through tartrate-resistant acid phosphatase staining and the expression levels of proteins RANKL and osteoprotegerin (OPG). We found that UA reduced IL-6 and TNF-α levels in vitro and in vivo, inhibited osteoclast differentiation, and decreased the RANKL/OPG ratio in periodontitis mice. Full article

Background: Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder caused by mutations in the DMD gene, leading to progressive muscle degeneration, loss of ambulation, and multi-systemic complications. Beyond its impact on mobility, DMD is associated with significant endocrine and metabolic dysfunctions that develop over time. Objective: To provide a comprehensive analysis of growth disturbances, endocrine dysfunctions, and metabolic complications in DMD including bone metabolism, considering the underlying mechanisms, clinical implications, and management strategies for daily clinical guidance. Methods: In this narrative review, an evaluation of the literature was conducted by searching the Medline database via the PubMed, Scopus, and Web of Science interfaces. Results: Growth retardation is a hallmark feature of DMD, with patients exhibiting significantly shorter stature compared to their healthy peers. This is exacerbated by long-term glucocorticoid therapy, which disrupts the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis and delays puberty. Obesity prevalence follows a biphasic trend, with increased risk in early disease stages due to reduced mobility and corticosteroid use, followed by a decline in body mass index (BMI) in later stages due to muscle wasting. Metabolic complications, including insulin resistance, altered lipid metabolism, and hepatic steatosis, further characterize disease burden. Osteoporosis and increased fracture risk, primarily due to reduced mechanical loading and glucocorticoid-induced bone resorption, are major concerns, needing early screening and intervention. The RANK/RANKL/OPG signaling pathway has emerged as a critical factor in bone deterioration, providing potential therapeutic targets for improving skeletal health. Conclusions: Growth and endocrine disorders in DMD are complex and multifactorial, requiring proactive monitoring and early intervention. Addressing these issues requires a multidisciplinary approach integrating endocrine, nutritional, and bone health management. Further research is essential to refine treatment strategies that mitigate growth and metabolic disturbances while preserving overall patient well-being. Full article

Background: The increasing prevalence of processed foods has significantly elevated dietary phosphorus intake globally, posing a risk to skeletal health. Elevated serum phosphate promotes parathyroid hormone (PTH) release, leading to bone resorption and decreased bone formation. Objective: This study investigated the influence of chronically elevated phosphorus intake on bone structure in rats with normal renal function, focusing on the Receptor Activator of Nuclear factor Kappa-B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) pathway and its related components, leucine rich repeat containing G protein-coupled receptor 4 (LGR4), and R-spondins (RSPOs). Methods: Rats were fed a high-phosphorus diet, followed by assessment of the bone microstructure and of the expression of key signalling molecules. Results: Elevated phosphorus intake induced significant bone deterioration, particularly in the trabecular bone compartment, associated with alterations in the RANK/RANKL/OPG pathway and in the LGR4 and RSPO1 and RSPO4 signalling components in bone. Moreover, we also observed changes in RANKL, RSPO1 and RSPO4 serum levels in the rats that had received a high-phosphorus diet. Conclusions: These findings highlight the detrimental impact of excessive dietary phosphorus on skeletal health, even without renal impairment, and suggest that components of this pathway, particularly RSPO1 and RSPO4, could serve as potential biomarkers of bone deterioration. The widespread consumption of phosphorus-rich processed foods underscores the importance of nutritional education to mitigate these skeletal risks in industrialized populations. Full article

Noonan syndrome (NS) is a genetic disorder characterized by distinctive craniofacial and skeletal features, short stature, mild to moderate developmental impairment, and multisystem involvement, notably affecting the cardiovascular, musculoskeletal, and endocrine systems. Although abnormalities of the bone matrix, as well as osteopenia and osteoporosis, are well recognized in individuals with NS and other RASopathies, the specific impact of RAS/MAPK pathway dysregulation on bone health remains poorly understood. Objectives: The aim of this study was to evaluate bone turnover and bone remodeling markers in a cohort of children with NS, to gain further insights into the bone status of these patients. Methods: In this cross-sectional, case-control study, we analyzed 28 children (20 males) with a molecular diagnosis of NS and 35 healthy subjects (21 males), matched by age and sex. We assessed markers of bone metabolism and bone turnover (calcium, phosphate, PTH, 25(OH)-vitamin D, osteocalcin, procollagen I N-propeptide-P1NP, bone alkaline phosphatase-BALP, C-telopeptides of type I collagen-CTX) and bone remodeling (RANKL, OPG, and sclerostin). Bone mineralization was measured at the lumbar spine (L2–L4) using dual-energy X-ray absorptiometry (DEXA). Results: Serum CTX levels were significantly higher in NS patients compared to controls (1.8 ± 0.7 vs. 1.3 ± 0.5 ng/mL, p = 0.0004). RANKL levels were higher in NS patients, although the difference did not reach statistical significance. No significant differences were found for OPG, sclerostin, or other markers of bone metabolism between patients and controls. Conclusions: Children with NS exhibit increased bone resorption, as indicated by elevated CTX levels, suggesting a potential imbalance in bone remodeling processes. Further studies are warranted to better define the impact of RAS/MAPK pathway dysregulation on bone health in this population. Full article

Oral cellular aging plays a critical role in the pathogenesis of chronic periodontitis and alveolar bone resorption. Although activating transcription factor 3 (ATF3) has been implicated as a senescence-associated factor, its specific role in periodontal ligament cell (PDLC) senescence remains unclear. Human PDLCs were exposed to lipopolysaccharide (LPS, 1 μg/mL) and nicotine (5 mM) for 3 days to induce senescence. ATF3 expression was silenced using siRNA. The expression of senescence-associated secretory phenotype (SASP) factors (IFNγ, IL6, IL8, TNFα, and IL1β) and the secretion of nitric oxide (NO) and prostaglandin E₂ (PGE₂) were assessed by RT-PCR and immunoassay. Conditioned media (CM) from these cells were applied to mouse bone marrow macrophages (BMMs) to evaluate osteoclast differentiation and bone resorption. In addition, key signaling pathways, including STAT3, ERK, NF-κB (p65), and AP-1, were investigated by Western blotting and immunofluorescence. ATF3 knockdown markedly reduced the LPS/nicotine-induced expression of SASP factors and decreased NO and PGE₂ levels. CM from ATF3-silenced PDLCs markedly inhibited osteoclast differentiation, as evidenced by reduced tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and diminished bone resorption. Moreover, ATF3 inhibition led to a decreased RANKL/OPG ratio and attenuated the phosphorylation of STAT3 and ERK, along with the reduced nuclear translocation of p65 and AP-1 components. These findings suggest that ATF3 plays a critical role in mediating cellular senescence and osteoclastogenesis in PDLCs. Targeting ATF3 may represent a novel therapeutic strategy for managing age-related oral diseases, such as chronic periodontitis. Full article

Negative-pressure wound therapy (NPWT) using vacuum-assisted closure (VAC) is a well known tissue defect bridging method that applies a vacuum pump to sterile, open-cell foam dressings via suction tubes. Although it has mostly been described for soft tissue use, there are also a few studies concerning its use on hard tissue. However, as oral and maxillofacial surgery has to deal with both soft and hard tissue, which lie next to each other in these regions, there is a particular need to assess the influence of negative pressure on bone. Therefore, the effects of different negative pressure levels (530 mbar and 725 mbar) and atmospheric pressure (1013 mbar) on bone tissue cultures and osteoblast cell cultures were investigated over periods of 1, 3, and 6 weeks. During the culture period, osteoblast growth and the tissue regeneration of bone defects were studied in vitro using tissue cultures that were histologically supplemented by cytological investigations and quantitative RNA expression studies. In the bone defect model, there was a faster defect reduction using NPWT; the effect was especially strong for 530 mbar. Compared to the control group, up to 30% more newly generated bone tissue was detected. This effect on the mineralization capacity was assessed by the mRNA expression of osteogenic marker genes, as well as the receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG), two multifaceted cytokines that regulate bone metabolism. The influence of negative pressure consequently resulted in a decreased RANKL/OPG ratio in osteoblasts. Associated with the upregulation of marker genes to up to 400%, including Col1, BMP4, OCN, and RUNX2, the decrease in the RANKL/OPG ratio to 41% indicates the stimulation of osteogenesis. Since VAC has been shown to be a safe and effective method to close wounds in general, these data suggest that patients suffering from compound bone and soft tissue defects in the maxillofacial area may benefit from an adapted therapy approach accelerating both soft and hard tissue regeneration. Full article

Bone metastases represent a critical complication in oncology, frequently indicating advanced malignancy and substantially reducing patient quality of life. This review provides a comprehensive analysis of the complex interactions between tumor cells and the bone microenvironment, emphasizing the relevance of the “seed and soil” hypothesis, the RANK/RANKL/OPG signaling axis, and Wnt signaling pathways that collectively drive metastatic progression. The molecular and cellular mechanisms underlying the formation of osteolytic and osteoblastic lesions are examined in detail, with a particular focus on their implications for bone metastases associated with breast, prostate, lung, and other cancers. A central component of this review is the categorization of pathological biomarkers into four types: diagnostic, prognostic, predictive, and monitoring. We provide a comprehensive evaluation of circulating tumor cells (CTCs), bone turnover markers (such as TRACP-5b and CTX), advanced imaging biomarkers (including PET/CT and MRI), and novel genomic signatures. These biomarkers offer valuable insights for early detection, enhanced risk stratification, and optimized therapeutic decision-making. Furthermore, emerging strategies in immunotherapy and bone-targeted treatments are discussed, highlighting the potential of biomarker-guided precision medicine to enhance personalized patient care. The distinctiveness of this review lies in its integrative approach, combining fundamental pathophysiological insights with the latest developments in biomarker discovery and therapeutic innovation. By synthesizing evidence across various cancer types and biomarker categories, we provide a cohesive framework aimed at advancing both the scientific understanding and clinical management of bone metastases. Full article