Osteoporosis is a progressive metabolic bone disease characterized by decreased bone density and microarchitectural deterioration, leading to an increased risk of fracture, particularly in postmenopausal women and the elderly. Increasing evidence suggests that inflammatory processes play a key role in the pathogenesis of osteoporosis and are strongly associated with the activation of osteoclasts, the cells responsible for bone resorption. In the present study, we investigated, for the first time, the influence of proinflammatory cytokines on the osteogenic differentiation, proliferation, and metabolic activity of primary human osteoblast-like cells (OBs) derived from the femoral heads of elderly patients. We found that all the proinflammatory cytokines, IL-1β, TNF-α, IL-6, and IL-8, enhanced the extracellular matrix mineralization of OBs under differentiation-induced cell culture conditions. In the cases of IL-1β and TNF-α, increased mineralization was correlated with increased osteoblast proliferation. Additionally, IL-1β- and TNF-α-increased osteogenesis was accompanied by a rise in energy metabolism due to improved glycolysis or mitochondrial respiration. In conclusion, we show here, for the first time, that, in contrast to findings obtained with cell lines, mesenchymal stem cells, or animal models, human OBs obtained from patients exhibited significantly enhanced osteogenesis upon exposure to proinflammatory cytokines, probably in part via a mechanism involving enhanced cellular energy metabolism. This study significantly contributes to the field of osteoimmunology by examining a clinically relevant cell model that can help to develop treatments for inflammation-related metabolic bone diseases.

Background: Thromboelastometry like ROTEM^® is a point-of-care method used to assess the coagulation status of patients in a rapid manner being particularly useful in critical care settings, such as trauma, where quick and accurate assessment of coagulation can guide timely and appropriate treatment. Currently, this method is not yet comprehensively available with sparse data on its effectiveness in resuscitation rooms. The aim of this study was to assess the effect of early thromboelastometry on the probability of mass transfusions and mortality of severely injured patients. Methods: The TraumaRegister DGU^® was retrospectively analyzed for severely injured patients (2011 until 2020) with information available regarding blood transfusions and Trauma-Associated Severe Hemorrhage (TASH) score components. Patients with an estimated risk of mass transfusion >2% were included in a matched-pair analysis. Cases with and without use of ROTEM^® diagnostic were matched based on risk categories for mass transfusion. A total of 1722 patients with ROTEM^® diagnostics could be matched with a non-ROTEM^® patient with an identical risk category. Adult patients (≥16) admitted to a trauma center in Germany, Austria, or Switzerland with Maximum Abbreviated Injury Scale severity ≥3 were included. Results: A total of 83,798 trauma victims were identified after applying the inclusion and exclusion criteria. For 7740 of these patients, the use of ROTEM^® was documented. The mean Injury Severity Score (ISS) in patients with ROTEM^® was 24.3 compared to 19.7 in the non-ROTEM^® group. The number of mass transfusions showed no significant difference (14.9% ROTEM^® group vs. 13.4% non-ROTEM^® group, p = 0.45). Coagulation management agents were given significantly more often in the ROTEM^® subgroup. Mortality in the ROTEM^® group was 4.1% less than expected (estimated mortality based on RISC II 34.6% vs. observed mortality 30.5% (n = 525)). In the non-ROTEM^® group, observed mortality was 1.6% less than expected. Therefore, by using ROTEM^® analysis, the expected mortality could be reduced by 2.5% (number needed to treat (NNT) 40; SMR of ROTEM^® group: 1:0.88; SMR of non-ROTEM^® group: 1:0.96; p = 0.081). Conclusions: Hemorrhage is still one of the leading causes of death of severely injured patients in the first hours after trauma. Early thromboelastometry can lead to a more targeted coagulation management, but is not yet widely available. This study demonstrated that ROTEM^® was used for the more severely injured patients and that its use was associated with a less than expected mortality as well as a higher utilization of hemostatic products.

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.

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.

Recent studies have demonstrated a close link between body composition and the development and progression of osteoporosis. Visceral fat, in particular, appears to influence bone loss through its pro-inflammatory properties. However, it remains unclear whether this mechanism is equally relevant across different forms of osteoporosis. To investigate whether body composition-especially visceral fat- differs between postmenopausal and senile osteoporosis. A total of 47 patients were prospectively enrolled. The senile osteoporosis group included patients aged ≥80 years (n = 20, mean age 87.4), the postmenopausal osteoporosis group included patients aged ≤75 years (n = 14, mean age 68.8), and the control group consisted of patients aged ≤75 years (n = 13, mean age 68.8) without osteoporotic fractures or other osteoporosis-specific risk factors. Participants underwent bioelectrical impedance analysis (BIA) to assess body composition. Additional assessments included basic osteological laboratory testing, geriatric evaluation, sarcopenia screening (SARC-F), and frailty screening using the Clinical Frailty Scale (CFS). Muscle mass, total body water, fat-free mass, and BMI were significantly reduced in the senile osteoporosis group compared to controls. Similar trends were observed in the postmenopausal group, though without statistical significance. Notably, the senile osteoporosis group had a significantly higher proportion of visceral fat relative to total fat mass than both the control and postmenopausal groups. Patients with senile and postmenopausal osteoporosis exhibit distinct differences in body composition compared to individuals without osteoporosis. In particular, the strong association between visceral fat and senile osteoporosis highlights a potential role for BIA in early risk detection and the development of tailored therapeutic strategies.

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.