Christoph Beyersdorf

Background/Objectives: Hip osteoarthritis (OA) is a highly prevalent musculoskeletal disorder associated with substantial functional impairment and healthcare burden. Although evidence-based clinical practice guidelines exist, including the 2021 guideline of the German Society for Orthopaedics and Trauma Surgery (DGOU), their implementation in routine practice remains incomplete. Large language models (LLMs) are increasingly consulted for guideline-related information, but the concordance of their answers with guideline recommendations is uncertain. This benchmark study evaluated the guideline concordance, comprehensiveness and length of answers generated by five widely used LLMs to questions derived from the 2021 German S3 guideline on evidence- and consensus-based indication criteria for total hip arthroplasty in hip OA (EKIT-Hip; AWMF register no. 187-001; lead society DGOU). It did not evaluate the effectiveness or safety of clinical decision support. Methods: In a cross-sectional, single-run benchmark study, 26 structured, context-free questions covering five of the six thematic complexes of the guideline (diagnosis and imaging; assessment of the level of suffering; evaluation of alternative therapeutic options; contraindications; optimisation of modifiable risk factors) were derived from the guideline recommendations and submitted between 9 November 2024 and 25 February 2025 through the consumer web interfaces of five LLM-based systems (GPT-4, GPT-4o, GPT-4o mini, Gemini Advanced and Consensus Premium), yielding 130 responses (one per system–question pair, each in a newly initiated chat session). Responses were evaluated by three board-certified orthopaedic surgeons blinded to model identity, using a four-point accuracy scale and a five-point comprehensiveness scale. Only a single consensus score per response was recorded, so inter-rater reliability could not be assessed. Response length was quantified in words and characters and benchmarked against the corresponding guideline text. Because all systems answered the same questions, ratings were analysed as paired, question-clustered data with cumulative-link mixed models (random intercept for question), Friedman and Cochran’s Q tests and question-level cluster-bootstrap confidence intervals; unpaired analyses were retained as sensitivity analyses. Results: Accuracy differed across systems (cumulative-link mixed model, likelihood-ratio χ²(4) = 49.0, p < 0.0001; paired Friedman χ²(4) = 41.7, p < 0.0001; unpaired Kruskal–Wallis sensitivity analysis H = 35.6, p < 0.0001). Mean accuracy was highest for GPT-4o (3.69 ± 0.55) and GPT-4 (3.62 ± 0.57), followed by GPT-4o mini (3.27 ± 0.78), Gemini Advanced (3.08 ± 0.84) and Consensus Premium (2.54 ± 0.71). Responses rated good or excellent accounted for 25/26 (96.2%) of GPT-4o and GPT-4 responses versus 15/26 (57.7%) for Consensus Premium. Comprehensiveness followed the same ordering (H = 33.0, p < 0.0001, ε² = 0.23), with GPT-4o achieving the highest mean score (4.31 ± 0.79). In the cumulative-link mixed model, the odds of a higher accuracy rating relative to Consensus Premium were 51.8 (95% CI 12.4–215.9) for GPT-4o and 35.4 (95% CI 9.2–136.4) for GPT-4; GPT-4o and GPT-4 did not differ (OR 1.47, multiplicity-adjusted 95% CI 0.23–9.21), and their paired mean difference in accuracy (0.08 points, 90% CI −0.11 to 0.26) lay within an equivalence margin of ±0.5 points. Responses rated poor were observed for Consensus Premium (2/26) and Gemini Advanced (1/26) and not for the ChatGPT variants (0/26 each; exact 95% CI 0–13.2%), so a clinically relevant error rate cannot be excluded for any system. Response length differed markedly (Friedman χ² = 47.3, p < 0.0001), ranging from 32.4 ± 11.5 words for Consensus Premium to 77.8 ± 24.9 words for GPT-4o, corresponding to 1.29-fold and 3.19-fold the length of the source guideline text, respectively. Conclusions: GPT-4o and GPT-4 received the highest ratings for accuracy and comprehensiveness in this single-run benchmark of static, context-free questions. These data describe guideline-concordant answer quality only; they do not establish clinical decision-support effectiveness or safety and do not support unsupervised clinical use of any evaluated system. Evaluation with standardised patient cases, repeated version-controlled runs, clinician-in-the-loop designs and prospective safety endpoints is required.

Bone-resident macrophages are increasingly recognized as regulators of bone metabolism, yet their contribution to primary human osteoblast cultures remains poorly understood. We investigated the functional relevance of CD14-positive cells in primary human osteoblast cultures obtained using two isolation methods. CD14-positive cells were depleted by magnetic-activated cell sorting, and non-depleted and depleted cultures were compared regarding cell viability, matrix mineralization, osteogenic and macrophage-associated marker expression, and responses to IL-1β, IL-6, and TNF-α. CD14 depletion reduced cell viability under growth conditions and significantly impaired matrix mineralization in cultures obtained with both isolation protocols. Depletion markedly decreased CD14 and other monocyte/macrophage-associated markers, while the osteogenic cell population was largely preserved, although marker-specific changes suggested altered osteoblast maturation. Despite reduced basal mineralization, IL-1β and TNF-α significantly enhanced mineralization in both non-depleted and CD14-depleted cultures, whereas IL-6 had no significant effect. These findings indicate that CD14-positive cells support basal osteoblast viability, maturation, and mineralization but are not required for the mineralization-promoting effects of IL-1β and TNF-α. Primary human osteoblast cultures should therefore be considered multicellular systems in which macrophage-like cells contribute substantially to basal osteogenic function.

Background/objective: Orthogeriatric co-management (OGCM) significantly improves outcomes in older adults with hip fractures; however, it remains unclear whether older adults with pelvic fractures can similarly benefit. This study aimed to compare clinical and geriatric profiles of older adults with hip fractures and pelvic fractures across relevant medical and geriatric domains. Demonstrating comparable profiles would support future prospective studies evaluating OGCM in patients with pelvic fractures. Methods: We retrospectively analyzed data from an ongoing observational study at our institution including 611 hospitalized adults aged 70 years or older with hip fractures ( n = 535) or pelvic fractures ( n = 76). Variables included age, functional status, comorbidity burden and incidence of delirium. Group comparisons were performed using the χ ² -test for categorical variables and the Kruskal–Wallis test for continuous variables. After Bonferroni adjustment, a p -value < 0.005 was considered statistically significant. The study was approved by the Ethics Committee of the Medical Faculty of Heinrich Heine University. Results: The median age was 85 years (interquartile range 80–89 years) and 69% of patients were female. Hip fractures accounted for 87.6% of cases and pelvic fractures for 12.4%. Both groups showed a high burden of comorbidity and geriatric impairment, including cognitive impairment, functional limitations, frailty and medical comorbidity. Most clinical parameters were comparable between groups. Although surgery was performed much more frequently in the hip fracture group, no significant differences in the overall medical and geriatric profiles were observed except for transfusion rate and postoperative delirium. Conclusion: Older adults with hip fractures and pelvic fractures have largely comparable clinical and geriatric profiles. Given the established benefits of OGCM in hip fracture care, a similar approach could also benefit patients with pelvic fractures. This hypothesis should be evaluated in future prospective interventional studies.

Osteal macrophages (“osteomacs”) are resident bone macrophages that support osteoblast differentiation and bone formation. Despite their importance in bone homeostasis, their function in human bone metabolism and osteoporosis remains poorly understood, largely due to the lack of a standardized isolation protocol. Here, we present a protocol for isolating primary human osteomacs from femoral head specimens obtained during arthroplasty. After the removal of bone marrow to minimize contamination with marrow-derived macrophages, bone fragments were enzymatically digested and osteomacs were isolated using CD14-based MACS^® or CD14/CD45/ALP-based FACS. Immunofluorescence confirmed macrophage identity and revealed expression of markers associated with both M1-like and M2-like activation states. Isolated cells displayed heterogeneous morphology and could be maintained in culture. This protocol enables reproducible isolation of human osteomacs and provides a foundation for translational studies investigating osteoimmune interactions in bone disease and osteoporosis.

Osteoporosis is the most prevalent metabolic bone disease globally, leading to an increased risk of fractures. Recent advances in ion channel research have shed light on the importance of mechanosensitive ion channels as novel players in these pathophysiological processes. This perspective discusses the involvement of the mechanosensitive ion channels TREK-1, Piezo, and volume-regulated anion channels (VRACs) as potential novel pharmacological targets for the treatment of osteoporosis. TREK-1, a mechanosensitive K2P channel is important for maintaining the resting membrane potential in many cells, including osteoblasts and osteoclasts. K2P channels regulate osteoblast proliferation and differentiation, as well as osteoclast activity, potentially modulating bone remodeling in osteoporosis. Piezo channels influence osteoblast differentiation and osteoclast activity by modulating calcium influx, which is crucial for osteogenic signaling pathways, such as Wnt/β-catenin and ERK1/2. Piezo1 activation promotes bone formation, while its deficiency leads to impaired osteogenesis and increased bone resorption. Volume-regulated anion channels have been shown to be involved in osteoblast adaptation to mechanical stress and macrophage polarization, which indicates their importance for bone homeostasis. Chronic inflammation is a major contributor to osteoporosis progression. Evidence of ion channel involvement in this process has emerged in recent years. Specifically, macrophage function in osteoporosis seems to be linked to ion channel activity. Inflammatory polarization of macrophages is a key player in inflammation-induced bone loss and can be driven by mechanosensitive ion channels. Modulating these ion channels may provide new therapeutic opportunities. Given the complexity of ion channel interactions in bone cells and their regulatory role in bone remodeling, understanding their precise function in osteoporosis is essential. Targeted modulation of mechanosensitive ion channels holds promise as a novel therapeutic approach to mitigate inflammation-driven bone loss and improve bone density. Further research into their role in osteoclasts and macrophage-driven bone degradation will aid in developing innovative osteoporosis treatments.

Zusammenfassung: Die Dual-Röntgen-Absorptiometrie (DXA) gilt international als Goldstandard in der Osteoporosediagnostik und -therapieüberwachung. Ihr zentrales Anwendungsgebiet ist die Bestimmung der Knochenmineraldichte (BMD). Die DXA hat sich in den letzten Jahren jedoch weiterentwickelt und ermöglicht heute eine multiparametrische Diagnostik, die neben der Knochendichte auch zusätzliche Parameter berücksichtigt. Voraussetzung für den klinischen Nutzen ist jedoch eine qualitativ hochwertige Durchführung und Befundung, da Fehler gravierende Auswirkungen auf Diagnostik und Therapieentscheidungen haben können. Aktualisierte Standards sollen eine strukturierte und qualitativ hochwertige Befundung sicherstellen. Zur Qualitätssicherung gehören standardisierte Protokolle und regelmäßige Schulungen des Personals sowie strukturierte Qualitätssicherungsprogramme nach ISCD-Empfehlungen. Weitere Einsatzgebiete der DXA umfassen die Knochengeometrie, Wirbelkörperfrakturen mit Vertebral fracture Analysis (VFA), atypische Femurfrakturen (AFF), kardiovaskuläre Risikostratifizierung, Körperzusammensetzung im Kontext von Adipositas oder Sarkopenie.

Proinflammatory cytokines such as IL-1β, IL-6, and TNF-α are key mediators of inflammatory bone loss and are commonly described as inhibitors of osteoblast function. However, their effects on osteogenesis remain controversial, likely due to the differences in the cell models and experimental settings in in vitro studies. We recently showed that these cytokines significantly enhanced the mineralization of primary human osteoblast-like cells (OBs). Here, we provide the first analysis of cytokine effects on the osteogenesis of the widely used human osteoblastic cell line hFOB 1.19 and compare them to primary OBs. Unexpectedly, all three cytokines significantly inhibited mineralization in hFOB 1.19 cells without affecting the proliferation. IL-1β and TNF-α also suppressed ALP activity, whereas IL-6 acted ALP-independent but increased the osteogenic marker expression despite the reduced mineralization, indicating a possible uncoupled differentiation and mineralization. Morphological and transcriptional analyses indicated that hFOB 1.19 cells represent an earlier osteogenic differentiation stage, while primary OBs show phenotypic heterogeneity and donor-dependent expression profiles. These data demonstrate that proinflammatory cytokines can have severely different effects on the osteogenesis of different cell models, supported by the highly contradictory findings reported in the literature. Nevertheless, elucidating the mechanisms underlying the inhibition of osteogenesis in hFOB 1.19 cells may provide important insights into the cell model and differentiation-stage-specific cytokine effects.

Introduction: Osteoporosis is the most prevalent musculoskeletal disease characterized by reduced bone mass, increasing fracture risk. Subtypes include postmenopausal and senile osteoporosis, each with distinct pathophysiological mechanisms. While postmenopausal osteoporosis is driven by estrogen deficiency, senile osteoporosis is associated with chronic inflammation, sarcopenia, and age-related metabolic changes. Recent studies suggest visceral fat may exacerbate inflammatory processes, contributing to bone loss. However, differences in body composition and cytokine profiles across osteoporosis subtypes remain underexplored. This study explores the impact of body composition (BC), particularly visceral fat, on osteoporosis subtypes and analyzes cytokine profiles to elucidate inflammatory contributions. Methods: This prospective study included 49 women aged 60 and older, who underwent treatment for a osteoporotic fractures of the hip or pelvis or coxarthrosis. They were divided into senile (n=20), postmenopausal (n=12), and control (n=15) groups. All participants underwent detailed clinical evaluation, laboratory diagnostics, and Body impedance analysis (BIA) to assess BC parameters, including muscle mass (MM), fat mass (FM) and visceral adipose tissue (VAT), Serum cytokine levels (IL-6, and CCL-2) were measured perioperatively in a second cohort of 103 patients to evaluate inflammatory burden. Results: Significant differences in body composition were observed across groups. Senile and postmenopausal osteoporosis patients exhibited the lowest MM (22.5 and 24.5 kg) compared to controls (27.7 kg; p<0.05). While VAT was not significantly different in absolute terms, the VAT/FM ratio was higher in the senile group (6.7) than in controls (4.2; p<0.05), indicating a relative increase in visceral fat. Postmenopausal patients demonstrated intermediate values (4.6, p=0.06 compared to controls) with similar trends.Inflammatory cytokine analysis revealed elevated IL-6 levels in both osteoporosis groups compared to controls (senile: 55 U/L; postmenopausal: 31 U/L; controls: 10.3 U/L; p<0.05). Interestingly, postmenopausal patients exhibited persistently high CCL-2 (176.9 U/L) levels postoperatively, surpassing senile and control groups (p<0.05). Discussion: This study highlights the distinct body composition and inflammatory profiles of senile and postmenopausal osteoporosis patients. Both groups exhibit increased relative VAT, consistent with elevated inflammatory cytokine levels. The study highlights the relevance of BIA measurement in the diagnosis and subtype differentiation of osteoporosis, emphasizing the potential role of visceral fat in the chronic inflammatory pathogenesis of osteoporosis. Future studies should investigate the potential use of visceral fat in the early detection and differentiation of osteoporosis in larger patient cohorts. Keywords: osteoporosis, body impedance analysis, visceral fat, inflammation Korrespondenzadresse: Christoph Beyersdorf, Universitätsklinikum Düsseldorf, Klinik für Orthopädie und Unfallchirurgie, Moorenstraße 5, 40225 Düsseldorf, Deutschland, E-Mail: Christoph.Beyersdorf@med.uni-duesseldorf.de Article published online: 21 March 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

Background: Osteoporosis, a skeletal disorder affecting nearly 20% of the global population, poses a significant health concern, with osteoporotic vertebral body fractures (VBF) representing a common clinical manifestation. The impact of osteoporotic sintering fractures in the thoracolumbar spine on the sagittal lumbar profile is incompletely understood and may lead to the onset of clinical symptoms in previously asymptomatic patients. Methods: This retrospective single-center study analyzed data from patients presenting with osteoporotic spine fractures between 2017 and 2022. Patient selection involved stringent inclusion and exclusion criteria, focusing on radiologically documented osteoporotic sintering fractures in the thoracolumbar junction (TH11-L2). Clinical parameters were recorded and analyzed, alongside lateral-view radiographic assessments utilizing the IDS 7-PACS^®-System (Sectra, Linköping, Sweden). Measurements included total lumbar lordosis, lordosis caudal to the fracture, kyphosis of the fractured vertebra, and sacral slope. Statistical analysis was conducted using SPSS 27 (IBM, Armonk, USA). Results: Thirty patients (73.3% female, 26.7% male) met the inclusion criteria, with an average age of 82.4 years. Analysis revealed a significant increase in kyphosis of the fractured vertebra in the thoracolumbar spine (p < 0.0001) following further sintering of osteoporotic VBF with increased lordosis caudal to the fracture (p < 0.0001). Total lumbar lordosis remained unchanged, alongside sacral slope measurements (p = 0.612 and p = 0.863, respectively). Conclusion: Progressive sintering of osteoporotic fractures in the thoracolumbar junction accentuates lordosis in underlying segments, potentially exacerbating degenerative changes and symptomatic manifestations. Thus, prioritizing interventions aimed at preventing progressive sintering and restoring sagittal balance is paramount in optimizing treatment outcomes for affected individuals.