Jiancheng Yang

Postmenopausal osteoporosis (PMOP) is frequently complicated by iron accumulation, which exacerbates bone loss. Baicalein, a natural flavonoid with iron‐chelating and antioxidant properties, has shown bone‐protective effects, but its role in iron‐overloaded PMOP remains unclear. This study investigated whether baicalein ameliorates iron‐accumulated PMOP by inhibiting osteoclastogenesis via Nrf2 activation. In vitro, bone marrow‐derived macrophages (BMMs) were induced into osteoclasts with RANKL under iron overload. Baicalein (10 μM) suppressed osteoclast differentiation, F‐actin ring formation, and bone resorption, reduced intracellular and mitochondrial ROS, lowered Fe ²⁺ and total iron content, and upregulated Nrf2 nuclear translocation and HO‐1 expression. These effects were abrogated by the Nrf2 inhibitor ML385 or Nrf2 siRNA. In vivo, an ovariectomized (OVX) mouse model with iron dextran injection (100 mg/kg/week) was used. Oral baicalein treatment (100 mg/kg/day) significantly prevented bone loss, improved bone microarchitecture and biomechanical properties, reduced iron deposition in bone, liver and spleen, lowered serum ferritin and bone ROS, and activated Nrf2 signaling in bone tissue. Co‐administration of ML385 reversed these protective effects. Collectively, baicalein ameliorates iron‐accumulated postmenopausal osteoporosis by activating the Nrf2 pathway, thereby inhibiting osteoclast differentiation and bone resorption. Baicalein represents a promising multi‐target candidate for treating PMOP, especially in patients with concomitant iron accumulation.

Postmenopausal osteoporosis (PMOP) is linked to iron accumulation. Melatonin has iron‐chelating and antioxidant properties, but its mechanism against osteoclastogenesis remains unclear. This study investigated whether melatonin suppresses osteoclast formation by targeting the iron/ROS‐CREB‐PGC‐1β‐mediated mitochondrial biogenesis pathway. In vitro , bone marrow‐derived macrophages (BMMs) were treated with RANKL and melatonin (10–1000 nM). Melatonin concentration‐dependently inhibited osteoclast differentiation, reduced intracellular ferrous and total iron levels, decreased ROS and oxidative stress markers, and suppressed mitochondrial biogenesis. Mechanistically, melatonin indirectly suppressed PGC‑1β expression via inhibition of CREB phosphorylation, without affecting PGC‑1α expression. The CREB activator forskolin reversed melatonin's effects, whereas the CREB inhibitor 666‐15 mimicked them. In vivo , ovariectomized (OVX) mice received weekly injections of iron dextran to model moderate iron overload, with or without oral melatonin. Melatonin ameliorated iron‑induced bone loss, improved bone microarchitecture and biomechanical properties, reduced tissue iron stores and bone ROS levels, and suppressed osteoclast mitochondrial biogenesis and the CREB/PGC‐1β pathway; these effects were counteracted by forskolin. In conclusion, melatonin prevents osteoclastogenesis and counters bone loss due to iron accumulation in estrogen‑deficient conditions by chelating iron, scavenging ROS, and blocking the iron/ROS‑activated CREB/PGC‑1β axis, thereby suppressing mitochondrial biogenesis. This study offers a mechanistic explanation for using melatonin as a possible treatment for PMOP, particularly when accompanied by iron overload.

Unloading-induced bone loss is a major medical challenge during long-duration human spaceflight, largely driven by suppressed osteoblast-mediated bone formation, and practical countermeasures are needed. Electromagnetic stimulation has shown benefits for bone repair, and its non-invasiveness supports potential space use; however, its single-modality efficacy remains limited. Here, we investigated a combined electromagnetic field (CEMF) integrating a static magnetic field (SMF, 0.4–0.6 T) and a pulsed electromagnetic field (PEMF, 0.38 ± 0.19 mT) to attenuate unloading-related bone loss and examine field-induced mechanical stimulation. Finite-element simulations mapped magnetic flux density, field gradient, induced current density, and Lorentz force density in bone tissue. CEMF was evaluated in vivo in hindlimb unloading (HLU) mice and in vitro in MC3T3-E1 osteoblasts. CEMF improved bone mineral density, trabecular and cortical microarchitecture, and mechanical properties in HLU mice, with increased osteoblast number and mineral apposition rate. In vitro, CEMF promoted osteogenic differentiation and upregulated COL1A1 and RUNX2. Transcriptome analysis suggested activation of ECM–integrin mechanical signaling and the PI3K–AKT pathway. These findings indicate that CEMF-induced multiphysics stimulation enhances osteogenic responses and may serve as a complementary, non-invasive countermeasure for spaceflight-associated bone loss.

Objective: This study aimed to investigate the protective effects and underlying mechanisms of baicalein against iron overload-induced osteoblast dysfunction and bone loss. Impact Statement: This research is the first to demonstrate that baicalein, a natural flavonoid, functions as a dual-action agent combining iron chelation and antioxidation to prevent iron overload-induced ferroptosis in osteoblasts, offering a novel therapeutic strategy for iron overload-related osteoporosis. Introduction: Iron overload contributes to osteoblast damage and osteoporosis through ferroptosis, an iron-dependent cell death pathway. Current treatments fail to simultaneously address iron accumulation and bone loss, highlighting the need for effective dual-function therapies. Methods: Using iron dextran-treated MC3T3-E1 osteoblasts and a murine iron overload model, we assessed the effects of baicalein on cell viability, osteogenic differentiation, ferroptosis markers, and the nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) pathway via biochemical assays, Western blot, and micro-computed tomography. Genetic and pharmacological inhibition of Nrf2 were applied to validate the mechanism. Results: Baicalein chelated iron, scavenged reactive oxygen species, and suppressed ferroptosis in osteoblasts, restoring differentiation under iron overload. It activated Nrf2 nuclear translocation and upregulated GPX4/solute carrier family 7-member 11 (SLC7A11) expression. In mice, baicalein reduced iron deposition, oxidative stress, and bone loss, and these effects were abolished by Nrf2 inhibition. Conclusion: Baicalein alleviates iron overload-induced osteoblast ferroptosis and osteoporosis by activating the Nrf2/GPX4 pathway, supporting its clinical potential as a therapeutic agent for iron-related bone disorders.

Background/Objectives: Fragility fractures, particularly in the vertebra and hip, are a significant health concern in the elderly, often associated with osteoporosis. Emerging evidence suggests a link between lipid profiles and bone health, but the characteristics of lipid biomarkers in patients with fragility fractures remain underexplored. Methods: This study analyzed serum lipid biomarkers, including total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in 10,540 patients aged 50 and older with either vertebral or hip fragility fractures. We compared lipid levels between the two fracture groups and examined the relationship between lipid profiles and baseline characteristics of patients. Results: Patients with vertebral fractures exhibited significantly higher serum levels of TC, TG, HDL-C, and LDL-C compared to those with hip fractures. These differences remained statistically significant after adjusting for confounding variables. Multivariable regression analysis revealed that age was inversely associated with TC, TG, and LDL-C, but positively associated with HDL-C. All lipid levels were significantly higher in women than in men. Time from fracture to admission and BMI were positively associated with TG levels and inversely associated with HDL-C. Vertebral fracture patients had a higher prevalence of abnormally high TC (3.03% vs. 0.78%), TG (9.15% vs. 3.54%), and LDL-C (2.80% vs. 1.04%), but lower prevalence of abnormally low HDL-C (20.53% vs. 26.66%; p < 0.001 for all). Conclusions: Our findings highlight distinct lipid profile characteristics in patients with vertebral and hip fragility fractures, suggesting that physiological or metabolic changes following different fracture types may differentially influence lipid metabolism. These insights may inform targeted prevention and management strategies for fragility fractures.

The accumulation of intracellular reactive oxygen species (ROS) is widely recognized to stimulate the development of osteoclasts, a crucial factor in the onset of osteoporosis. The ROS scavenging capability of Prussian blue nanoparticles (PBNPs) is exceptional, and they possess excellent biocompatibility. However, the effects of PBNPs on osteoporosis remain unknown. Present study aimed to investigate whether PBNPs could inhibit osteoclast differentiation and prevent ovariectomy (OVX)‐induced bone loss by suppressing ROS. In vitro experiments demonstrated that PBNPs attenuated osteoclastogenesis and downregulated the expression of osteoclast‐related genes. Mechanistically, PBNPs reduce cellular ROS by blocking RANKL‐induced ROS generation and increasing the expression of ROS scavenging enzymes, which in turn block the NF‐κB, ERK, JNK, and p38 pathways, thereby reducing NFATc1 signaling. According to in vivo experimental results, OVX caused a significant rise in ROS in the bone marrow, an increase in osteoclastic number on the bone surface, and substantial bone loss; however, PBNPs significantly reduced ROS and successfully protected OVX‐induced bone damages. In conclusion, this study showed for the first time that PBNPs prevented OVX‐induced bone loss and attenuate osteoclastogenesis, indicating that PBNPs may be a viable alternative therapy for the management of osteoclast‐associated bone disorders.