Search Results (833)

Background: Osteoporosis is increasingly understood as a complex population health condition shaped by interacting behavioral, metabolic, pharmacological, and healthcare system determinants rather than isolated skeletal risk factors. However, comparative studies integrating these dimensions across distinct healthcare and sociocultural settings remain scarce. We aimed to characterize cross-national differences in osteoporosis-related risk clustering between Romanian and Tunisian adults using an integrative multidimensional framework. Methods: We performed a comparative cross-sectional analysis of harmonized data from two pharmacy-based studies conducted in Romania and Tunisia, including adults aged ≥ 40 years (n = 349). Osteoporosis-related knowledge, lifestyle and metabolic risk factors, pharmacological exposures, preventive behaviors, and treatment patterns were assessed. Multivariable regression and mediation analyses were used to identify independent predictors of screening uptake and to evaluate the relationship between knowledge and preventive behavior. An exploratory cumulative preventive deficit score was used to estimate overall preventive burden within the pharmacy-based study sample. Results: Romanian participants demonstrated significantly higher osteoporosis knowledge than Tunisian participants (8.90 ± 2.20 vs. 7.83 ± 2.99; p < 0.001); however, knowledge was not independently associated with Dual-Energy X-ray Absorptiometry (DXA) uptake and did not mediate country-related differences in screening behavior. Compared with the Romanian cohort, the Tunisian cohort exhibited lower DXA screening rates (11.2% vs. 22.8%; p = 0.005), lower vitamin D supplementation (11.9% vs. 38.6%; p < 0.001), greater sedentary behavior, and a significantly higher cumulative preventive deficit burden (3.39 ± 1.08 vs. 2.77 ± 1.26; p < 0.001). Medication-related osteoporosis risk was also greater in Tunisia, particularly due to markedly higher corticosteroid exposure (7.5% vs. 0.5%; p = 0.002). Despite this less favorable preventive profile, the treatment gap among participants with diagnosed osteoporosis was significantly lower in Tunisia than in Romania (4.8% vs. 42.9%; p = 0.003). Conclusions: Distinct but convergent osteoporosis-related risk patterns were identified across the two populations, suggesting that osteoporosis vulnerability emerges through context-specific clustering of behavioral, pharmacological, and healthcare-access determinants rather than through isolated risk factors alone. The dissociation between knowledge and preventive behavior highlights the limited impact of awareness-based strategies when structural barriers remain unaddressed. These findings support a shift toward integrated, population-tailored osteoporosis prevention models that incorporate healthcare-system, medication-related, and behavioral determinants, in addition to conventional educational approaches. Full article

Osteoporotic vertebral fractures (OVFs) are the most common osteoporotic fracture type and remain substantially underdiagnosed despite their diagnostic, prognostic, and therapeutic importance. This review examines OVFs as sentinel events in osteoporosis, emphasizing their role in diagnosis, fracture-risk stratification, treatment selection, and secondary fracture prevention. This narrative review synthesizes evidence from contemporary clinical practice guidelines, epidemiological studies, randomized controlled trials, systematic reviews, meta-analyses, and selected observational studies addressing imaging and artificial-intelligence-assisted detection. References were selected based on clinical relevance, methodological rigor, and recency, in keeping with the conventions of a focused narrative review rather than a systematic review. OVFs frequently occur without classic osteoporosis-range bone mineral density and often remain clinically silent or incidentally detected. Nevertheless, they independently predict future vertebral, hip, and non-OVFs, particularly during the early post-fracture period. Vertebral fracture assessment on dual-energy X-ray absorptiometry (DXA), opportunistic CT screening, standardized radiology reporting, and AI-assisted detection may improve case finding. Management should combine acute pain control, rehabilitation, appropriate use of vertebral augmentation in selected patients, pharmacological osteoporosis therapy, and structured secondary prevention. Patients with recent or multiple OVFs often meet criteria for high or very-high fracture risk and may benefit from anabolic-first or sequential therapy strategies. Fracture Liaison Services provide a system-level model to close the diagnosis and treatment gap. Recognizing OVFs as actionable markers of skeletal fragility is essential for reducing subsequent fracture burden. Full article

Background: COVID-19-related mobility restrictions may have affected physical activity and post-fracture care in older adults. This study compared outcomes before and after age-based mobility restrictions, focusing on reported activity, documented combined postoperative physiotherapy and anti-osteoporotic pharmacologic treatment, and secondary fragility fractures. Methods: This retrospective single-center pre–post study included patients aged 65 years or older who underwent bipolar hemiarthroplasty for low-energy osteoporotic femoral neck fracture. Patients treated during the year before restrictions were compared with those treated during the post-restriction year. Outcomes included reported pre-fracture activity category, all-cause mortality, mobility among survivors, documented combined postoperative physiotherapy and anti-osteoporotic pharmacologic treatment, and secondary fragility fractures. Results: The pre-pandemic and post-restriction groups included 65 and 122 patients, respectively. Regular outdoor walking/activity before fracture was less frequent in the post-restriction group than in the pre-pandemic group (45.1% vs. 72.3%; p < 0.001), whereas home-limited activity was more frequent (54.9% vs. 27.7%). All-cause mortality during follow-up was 24.6% and 29.5%, respectively (p = 0.499). Mobility among survivors did not differ significantly (p = 0.832). Among survivors, documented combined postoperative physiotherapy and anti-osteoporotic pharmacologic treatment was uncommon: 14.3% and 17.4%, respectively (p = 0.809). Secondary fragility fractures were recorded only in the post-restriction group (8/86 survivors, 9.3%; p = 0.051). Conclusions: In this retrospective pre–post comparison, the post-restriction group showed a lower proportion of reported outdoor activity, while documented combined postoperative physiotherapy and anti-osteoporotic pharmacologic treatment remained uncommon among survivors. Secondary fragility fractures were observed only in the post-restriction group and should be interpreted with caution, given the exploratory design and limited number of events. Structured rehabilitation referral, osteoporosis treatment, fall-prevention strategies, and follow-up pathways remain important components of post-fracture care following femoral neck fracture. Full article

The gut microbiota and its metabolites, as components of the gut–bone axis, play a pivotal role in regulating skeletal homeostasis through the bidirectional communication network. In this systematic review, evidence was collected from mainstream databases following standardized inclusion/exclusion criteria for screening, to comprehensively retrieve and screen eligible studies from multiple mainstream databases according to standardized inclusion and exclusion criteria, and systematically summarize current research progress on plant-derived bioactive compounds targeting the gut–bone axis for skeletal health regulation. This review systematically explores the underlying mechanisms of the gut–bone axis and critically evaluates the regulatory effects and therapeutic potential of plant-derived bioactive compounds. Particular attention is given to targeted interventions involving prebiotics, probiotics, synbiotics, and plant-rich diets or functional foods. Among these interventions, synbiotics represent the most successful strategy and show the most prominent therapeutic possibilities in bone-related disorders. Different from single prebiotics (only nourish endogenous intestinal microbes), individual probiotics (easy to be degraded in gastrointestinal tract with poor colonization) and ordinary plant-rich diets (unfixed effective dosage and weak targeting property), synbiotics combine prebiotic carriers and viable probiotic strains to produce complementary advantages, which is the core reason for its outstanding therapeutic prospect against bone diseases. Synbiotics exert synergistic effects on gut microecology, mineral absorption, and immune regulation, leading to more robust and consistent improvements in bone health than single prebiotics, probiotics, or general plant-rich diets. They have been verified in preclinical and clinical studies to ameliorate osteoporosis and related skeletal diseases via the gut–bone axis. These strategies offer novel insights into the prevention and treatment of bone metabolic disorders, such as osteoporosis, by targeting the gut–bone axis with phytochemicals. Key outcomes of this review include that synbiotics, soy isoflavones, naringin, curcumin, and resveratrol effectively improve bone mineral density, restore gut microbiota balance, and inhibit pathological bone resorption via the gut–bone axis. Collectively, the above bioactive substances realize bone protection mainly by reshaping gut flora, elevating mineral uptake and suppressing excessive osteoclast activity. Representative cases include soy isoflavones mitigating estrogen-deficient bone loss in OVX models, naringin improving the trabecular microarchitecture, and probiotic BL-11 promoting longitudinal bone growth in children. Future directions will focus on clarifying dose–response relationships, developing standardized synbiotic formulations, constructing microbiome-guided precision diets, and conducting large-sample randomized controlled trials to translate plant-derived compounds into clinical therapies. Full article

Background: Natto, a well-known fermented soybean product beneficial for bone health, remains unclear in its mechanism. Methods: This study investigated its effect on secondary osteoporosis (OP) in mice. Results: Natto significantly inhibited weight loss, bone quality deterioration, and bone morphological damage, and regulated OPG/RANKL pathway protein expression (p < 0.05) in OP mice. Analysis of 16S rRNA revealed that natto increased gut microbiota α-diversity and the abundance of Sutterella, Roseburia, and Coprococcus, while reducing harmful bacteria such as Streptococcus, Shigella, and Helicobacter. These microbial changes positively correlated with body weight, bone size, and serum osteogenic metabolism in OP mice. Serum metabolomics showed differential metabolites of the natto group enriched in PPAR signaling and primary bile acid biosynthesis. Verification by mRNA and ELISA indicated that the upregulated liver and circulating PPARα by natto may regulate downstream bile acid pathways, linking gut microbiota to multi-organ metabolic functions. Conclusions: In summary, natto may act on gut microbiota to alleviate bone loss via the “gut microbiota–bile acid–OPG/RANKL” network, targeting multiple organs including gut, liver, and bone. This provides a theoretical basis for natto dietary intervention in osteoporosis prevention through the gut–bone axis. Full article

Background: Unmet healthcare needs are a significant public health concern among older adults, particularly those with chronic conditions such as osteoporosis. This study aimed to identify several key factors associated with unmet healthcare needs among older adults with osteoporosis using Andersen’s behavioral model. Methods: This observational, cross-sectional study examined data from the 2025 Korea Community Health Survey, analyzing responses from 20,988 individuals aged ≥ 65 years with physician-diagnosed osteoporosis. General characteristics were analyzed using descriptive statistics in terms of frequencies and percentages. Variables were categorized into predisposing, enabling, and need factors. Complex sample analyses were performed using the Rao–Scott chi-square test and multivariable logistic regression. Results: In the multivariable analysis, female sex (adjusted odds ratio [aOR] = 1.44, 95% confidence interval [CI]: 1.08–1.91), poor health literacy (aOR = 1.56, 95% CI: 1.31–1.87), and rural residence (aOR = 1.36, 95% CI: 1.18–1.58) were significantly associated with higher odds of unmet healthcare needs. Among the need factors, fall experience (aOR = 1.56, 95% CI: 1.34–1.83), pain or discomfort (aOR = 2.40, 95% CI: 1.93–2.99), and elevated stress (aOR = 2.37, 95% CI: 2.02–2.79) were also significantly associated with unmet healthcare needs. Conclusions: Beyond accessibility, unmet healthcare needs among older adults with osteoporosis in Korea were associated with cognitive, health-related, and regional factors. Interventions should prioritize improving health literacy, managing pain and psychological distress, and strengthening osteoporosis care pathways, specifically focusing on follow-up care and fragility fracture prevention. Full article

Background: Menopausal hormone therapy (MHT) effectively relieves vasomotor symptoms, but its cardiovascular safety remains influenced by timing, formulation, and route of administration. Methods: This narrative review summarizes evidence from major randomized trials (WHI, HERS, ELITE, DOPS) and observational studies, along with mechanistic data on the vascular and metabolic effects of MHT. Results: Although early studies suggested cardioprotection, randomized trials showed no cardiovascular benefit, and in some cases, increased risks of coronary events, stroke, and venous thromboembolism, particularly in older women or those with established cardiovascular disease. The “timing hypothesis” indicates that early initiation after menopause may have neutral or modestly favorable effects, whereas late initiation is associated with adversity. Oral estrogen is linked to higher thromboembolic and stroke risk compared with transdermal formulations. Evidence on atrial fibrillation and heart failure remains limited. Conclusions: MHT should not be used for cardiovascular disease prevention. Current evidence suggests that younger women in the early postmenopausal period may derive the greatest benefit with the lowest risk from individualized hormone therapy regimens, particularly those using transdermal estrogen. Treatment decisions should be guided by careful cardiovascular risk assessment and targeted to symptom relief and osteoporosis prevention. Full article

Background/Objectives: Osteoporosis-related fragility fractures are sentinel events that should trigger timely secondary prevention, yet post-fracture care remains inconsistent. Leveraging the NIH All of Us Research Program, we quantified initiation of osteoporosis pharmacotherapy after fragility fracture and explored associations by age, sex at birth, race, and ethnicity. Methods: Retrospective cohort study using All of Us Controlled Tier data (v8) included adults aged 45 to 100 years with an index fragility fracture using prespecified OMOP concept sets intended to capture fractures commonly associated with osteoporosis. A new-user design excluded participants with any osteoporosis pharmacotherapy in the 365 days before fracture; participants required at least 180 days of follow-up. The primary outcome was initiation of osteoporosis pharmacotherapy (bisphosphonates, denosumab, or anabolic agents) within 180 days. Secondary outcomes were completion of dual-energy x-ray absorptiometry (DXA) and bone-health laboratory testing within 180 days. Multivariable logistic regression estimated adjusted odds ratios (OR) for each outcome by age at fracture, sex at birth, race, and ethnicity. Results: Among 1492 eligible participants, 87 initiated pharmacotherapy within 180 days (5.83%). After adjustment, older age was associated with higher odds of initiation (OR 1.04 per year; 95% CI 1.02 to 1.05). Male participants had markedly lower odds of pharmacotherapy initiation (OR 0.20; 95% CI 0.11 to 0.37) and DXA screening (OR 0.22; 95% CI 0.15 to 0.32) compared with female participants. In exploratory adjusted models, we did not detect an independent association between race and pharmacotherapy initiation (White vs. Black/African American OR 1.01; 95% CI 0.49 to 2.09), while White participants had higher odds of DXA screening than Black/African American participants (OR 1.79; 95% CI 1.02 to 3.28). Conclusions: In this diverse national EHR-based cohort, initiation of osteoporosis pharmacotherapy after fracture was uncommon, highlighting a substantial secondary prevention gap. In exploratory adjusted models, male sex was associated with lower odds of pharmacotherapy initiation and DXA receipt, while White participants had higher odds of DXA receipt than Black participants. System-level post-fracture pathways, including fracture liaison services and EHR-based prompts, may improve equitable identification and treatment of osteoporosis for All of Us participants and their communities. Full article

Objective: Posterior lumbar interbody fusion (PLIF), posterolateral fusion (PLF), and Hybrid fusion are widely used fusion procedures for lumbar degenerative diseases (LDDs). Postoperative complications dominated by cage migration (CM) and adjacent segment degeneration (ASD) remain major challenges. This study aimed to identify and compare the independent risk factors for CM and ASD in PLIF, PLF, and Hybrid fusion, so as to provide evidence-based references for preoperative evaluation, surgical selection, and complication prevention in clinical practice. Methods: A retrospective cohort study was conducted in patients who underwent PLIF, PLF, or Hybrid fusion for LDDs at our institution. Demographic data (age, gender, and body mass index [BMI]), lifestyle factors (smoking and insobriety), comorbidities (hypertension, diabetes, hyperuricemia, osteoporosis, and hypoalbuminemia), surgical parameters (operative time, intraoperative blood loss, fusion segments, and lumbar lordosis angle), radiological indices (Pfirrmann grading of intervertebral disc degeneration and relative disc height), and biological markers (C-reactive protein/lymphocyte ratio [CLR], procalcitonin [PCT], and serum amyloid A [SAA]) were collected. Patients were stratified into complication and non-complication groups based on the occurrence of CM or ASD. Univariate and binary logistic regression analyses were performed to determine independent risk factors for postoperative complications. Results: A total of 203 patients were enrolled, including 80 cases with complications in the PLIF group, 64 in the Hybrid group, and 59 in the PLF group. No significant differences were noted in the distribution of complication types among the three groups (p = 0.179). Univariate analysis revealed that BMI, osteoporosis, the Pfirrmann grading of superior adjacent disc degeneration, lumbar lordosis angle, operative time, and intraoperative blood loss were significantly associated with postoperative complications across all three surgical groups (p < 0.05). Binary logistic regression analysis confirmed that elevated BMI (PLIF: OR = 1.18, 95%CI: 1.05–4.38; PLF: OR = 1.19, 95%CI: 0.76–2.18; Hybrid: OR = 1.14, 95%CI: 1.07–2.54), osteoporosis (PLIF: OR = 6.86; PLF: OR = 7.62; Hybrid: OR = 5.62), advanced superior adjacent disc degeneration (PLIF: OR = 8.04; PLF: OR = 4.49; Hybrid: OR = 2.87), prolonged operative time, and increased intraoperative blood loss were independent risk factors for postoperative complications. In contrast, age, gender, smoking, insobriety, hypertension, diabetes, CLR, PCT, and SAA were not identified as risk factors (p* > 0.05). Conclusions: Elevated BMI, osteoporosis, pre-existing superior adjacent disc degeneration, prolonged operative time, and increased intraoperative blood loss are shared independent risk factors for CM and ASD following PLIF, PLF, and Hybrid fusion for LDDs. Targeted interventions addressing these factors may reduce postoperative complication rates and improve patient outcomes. Full article

Background: We previously reported that knocking down the ubiquitin E3 ligase LNX2 in bone marrow monocytes by shRNAs attenuated osteoclastogenesis in vitro. However, the role of LNX2 in the regulation of osteoclasts and bone homeostasis in vivo remains unknown. Methods: In this study, we generated myeloid Lnx2 conditional knockout mice by crossing Lnx2-flox mice with LysM-Cre mice. The role of LNX2 was verified through in vitro osteoclast induction experiments using mononuclear macrophages and experiments on estrogen-deficient osteoporosis models. Results: Micro-CT and histological analysis unveiled that loss of Lnx2 in osteoclast precursor cells decreased osteoclast numbers and increased trabecular bone mass in mice. Moreover, Lnx2 deficiency prevented bone loss in an ovariectomized mouse model of postmenopausal osteoporosis. In vitro mechanistic studies identified that the loss of Lnx2 had little effect on cell proliferation but significantly inhibited the formation of osteoclasts and bone resorption. Furthermore, the deletion of Lnx2 decreased the expression of NOTCH2 and its downstream HES1 via enhancing the level of the NOTCH2 inhibitor, NUMB. Conclusions: Our findings elucidate an important role of Lnx2 in the regulation of osteoclasts and bone metabolism and indicate that Lnx2 is a potential therapeutic target for the treatment of osteoporosis. Full article

Osteoporosis is an age-related metabolic bone disorder characterized by an imbalance between bone resorption and formation. Natural polyphenols have gained attention as potential complementary strategies for its prevention. In this study, we investigated the effects of a sustainable, polyphenol-rich extract from red grape pomace (GPE) on human mesenchymal stem cell (MSC) fate and its underlying mechanisms of action. We found that GPE significantly promoted osteogenic differentiation while suppressing adipogenic differentiation in canonical bone marrow-derived MSCs (BMSCs). This biological effect was preserved in adipose tissue-derived MSCs (AdMSCs) obtained from elderly patients (>65 years) at high cardiovascular risk. Mechanistically, GPE downregulated adipogenic markers (PPARγ, CD36 and FABP4) and enhanced osteogenic markers (RUNX2, ALP, OSX, BMP-2, OPN, COL1A1 and OCN). Moreover, GPE activated NRF2-dependent redox signaling, as evidenced by increased NRF2 nuclear translocation and transcriptional activity. Accordingly, GPE treatment significantly upregulated, or consistently increased, the expression of multiple NRF2 target genes, including HO-1, GPX, CAT, GCLC, and NQO1. Importantly, pharmacological inhibition of NRF2 attenuated GPE-induced ALP activity, confirming NRF2 as a key mediator of its osteogenic effects. Overall, grape pomace-derived polyphenols act as upstream modulators of redox-sensitive and osteogenic transcription factors, rebalancing MSC differentiation toward osteogenesis and mitigating age-related bone fragility. Full article

Hajdu–Cheney syndrome (HCS) is a rare genetic skeletal disorder caused by truncating variants of NOTCH2, characterized by progressive bone resorption and marked phenotypic heterogeneity. Despite advances in understanding Notch signaling in skeletal biology, longitudinal clinical data tracking disease evolution from early childhood through adolescence are lacking. Here, we report a rare longitudinal intrafamilial observation of HCS in a mother and her son carrying the same NOTCH2 pathogenic variant, providing novel insights into disease evolution and therapeutic response. Over extended follow-up, the son exhibited early vertebral fragility despite preserved or supranormal bone mineral density (BMD), whereas the mother developed severe osteoporosis, progressive acro-osteolysis, and multiple vertebral fractures. Longitudinal analysis revealed a dissociation between vertebral fragility and densitometric decline, challenging the paradigm that low BMD is the primary driver of skeletal morbidity in HCS. Treatment responses differed between the two patients, with bisphosphonate therapy in the son associated with stabilized BMD without altering vertebral structural progression, and denosumab in the mother associated with increased BMD, but not preventing progression of acro-osteolysis. Additionally, the emergence of extra-skeletal features during adolescence expands the phenotypic spectrum of HCS and suggests previously unrecognized systemic involvement. These data highlight intrinsic limitations of current therapeutic strategies and emphasize the need for targeted interventions addressing sustained Notch2 activation. Our findings contribute to the understanding of the natural history and therapeutic challenges of HCS, providing the framework for future mechanistic and translational research. Full article

Background: Recent studies suggest that prunes are one of the most effective fruits for preventing and reversing bone loss. Objectives: The purpose of the present systematic review was to summarize the evidence from the randomized controlled studies on the effect of prunes on bone health in humans and to pool the results in a meta-analysis. The hypothesis of the present review was that bone mineral density of the pulled intervention group would be higher than that of the control group. Methods: We conducted a systematic review of randomized controlled studies with a three-level mixed-effects meta-analysis. Results: Of two hundred and eighty-four studies that were initially identified in PubMed, Scopus, and Web of Science using the search words, eleven papers (747 participants) were considered eligible. The effect of prune intervention in postmenopausal women was borderline significant at the lumbar spine, with BMD slightly higher in the intervention group (SMD [95% CI] = 1.30 [−0.03, 2.63]; I² = 98%; p < 0.001). No significant differences were observed at other individual BMD sites. Heterogeneity across studies was high for all measured sites. The difference between the intervention and control groups in the levels of bone formation and resorption markers was not significant. The risk of bias of the included randomized controlled studies, assessed by the RoB v.2 tool, was low. Conclusions: Our meta-analysis provides preliminary evidence of modest skeletal benefits associated with consumption of 50–100 g of prunes, particularly at the lumbar spine, a trabecular-rich site. However, the overall body of research remains limited. Full article

Background/Objectives: Older patients with fractures often present with a complex interplay of factors associated with frailty and functional decline. The emerging concept of Orthogeriatric Fracture Syndrome (OFS) aims to characterize these distinct relationships of pathologies and outcomes. Despite increasing recognition of OFS in clinical practice, due to the distributed nature of fragility factors across medical disciplines, it remains poorly defined in the literature. Methods: We used large-scale text mining of 26 million PubMed abstracts to quantify the occurrence and interrelationship of OFS-related concepts across all disciplines in biomedical research. Results: OFS terms were more prevalent in fragility fractures than in other fracture types, particularly osteoporosis (0.52 vs. 0.09, p < 0.05). In pairwise keyword correlation (Pearson φ), the correlations presented between OFS keywords are comparable to the ones in the more established metabolic syndrome (e.g., φ = 0.07 between stroke and hypertension, p < 0.05). For OFS, osteoporosis emerged as the central node linking OFS outcomes and pathologies, correlating with fragility fracture (φ = 0.176, p < 0.05) and sarcopenia (φ = 0.03, p < 0.05). Sarcopenia in turn correlated with gait (φ = 0.04, p < 0.05), malnutrition (φ = 0.05, p < 0.05), and frailty (φ = 0.032, p < 0.05). Old age keywords showed substantially higher association with OFS keywords (e.g., φ = 0.06 for elderl* and hip fracture, p < 0.05) than with metabolic syndrome terms (elderl* and insulin resistance, p > 0.05). Conclusions: Overall, the analysis showed statistically significant associations between keywords representing OFS outcomes, pathologies and old age. The combined occurrence of osteoporosis, sarcopenia, frailty and risk of falls may help conceptually identify older adults at risk and inform preventive measures. This large-scale bibliometric analysis supports OFS as a conceptually coherent, proposed theoretical framework for cross-disciplinary awareness and coordinated care, with a literature-level organizational pattern comparable to metabolic syndrome, however, pending prospective clinical validation. This study reframes fragility fractures as the endpoint of a broader, potentially modifiable risk constellation and underscores the need for further clinical and epidemiological validation. Full article

Excessive osteoclast activity drives inflammatory bone loss in osteoporosis, rheumatoid arthritis, and periodontitis. Natural compounds represent promising therapeutic candidates with favorable safety profiles; however, few exhibit pathway-biased mechanisms of action. Here, we report that angelic acid (AA), a naturally occurring unsaturated monocarboxylic acid, potently inhibits RANKL-induced osteoclastogenesis. This effect occurs with an IC₅₀ of 1.9 µM without cytotoxicity. Mechanistically, AA selectively suppressed RANKL-activated phosphorylation of ERK1/2, p38, and JNK (all three MAPK branches), while leaving NF-κB transcriptional activity unaffected. This preferential MAPK suppression disrupted downstream NFATc1 nuclear translocation, thereby preventing NFATc1-driven transcription of osteoclast-specific effector genes including TRAP, cathepsin K, and Atp6v0d2. These findings identify AA as a novel inhibitor of the RANKL–MAPK–NFATc1 axis, providing a mechanistic foundation for its therapeutic development in osteoporosis and other osteolytic diseases. Full article