Given the potential fundamental function of osteal macrophages in bone pathophysiology, we study here their precise function in experimental osteoporosis. Gene profiling of osteal macrophages from ovariectomized mice demonstrated the upregulation of genes that were involved in oxidative stress, cell senescence, and apoptotic process. A single-cell RNA-Seq analysis revealed that osteal macrophages were heterogeneously clustered into 6 subsets that expressed proliferative, inflammatory, antiinflammatory, and efferocytosis gene signatures. Importantly, postmenopausal mice exhibited an increase in subset 3 that showed a typical gene signature of cell senescence and inflammation. These findings suggest that the decreased production of estrogen due to postmenopausal condition altered the osteal macrophage subsets, resulting in a shift toward cell senescence and inflammatory conditions in the bone microenvironment. Furthermore, adoptive macrophage transfer onto calvarial bone was performed, and mice that received oxidatively stressed macrophages exhibited greater osteolytic lesions than control macrophages, suggesting the role of these cells in the development of inflammaging in the bone microenvironment. Consistently, depletion of senescent cells and the oxidatively stressed macrophage subset alleviated the excessive bone loss in postmenopausal mice. Our data provided insight into the pathogenesis of osteoporosis and shed light on a therapeutic approach for the treatment or prevention of postmenopausal osteoporosis.

Pyogenic spondylodiscitis can cause severe osteolytic and destructive lesions in the spine. Elderly or immunocompromised individuals are particularly susceptible to infectious diseases; specifically, infections in the spine can impair the ability of the spine to support the trunk, causing patients to be bedridden, which can also severely affect the physical condition of patients. Although treatments for osteoporosis have been well studied, treatments for bone loss secondary to infection remain to be elucidated because they have pathological manifestations that are similar to but distinct from those of osteoporosis. Recently, we encountered a patient with severely osteolytic pyogenic spondylodiscitis who was treated with romosozumab and exhibited enhanced bone formation. Romosozumab stimulated canonical Wnt/β-catenin signaling, causing robust bone formation and the inhibition of bone resorption, which exceeded the bone loss secondary to infection. Bone loss due to infections involves the suppression of osteoblastogenesis by osteoblast apoptosis, which is induced by the nuclear factor-κB and mitogen-activated protein kinase pathways, and osteoclastogenesis with the receptor activator of the nuclear factor-κB ligand-receptor combination and subsequent activation of the nuclear factor of activated T cells cytoplasmic 1 and c-Fos. In this study, we review and discuss the molecular mechanisms of bone loss secondary to infection and analyze the efficacy of the medications for osteoporosis, focusing on romosozumab, teriparatide, denosumab, and bisphosphonates, in treating this pathological condition.

Background/Objectives: Periprosthetic osteolysis is the primary cause of arthroplasty failure in the majority of patients. Mechanistically, wear debris released from the articulating surfaces of a prosthesis initiates local inflammation and several modes of regulated cell death programs, such as ferroptosis, which represents a promising therapeutic target in various chronic inflammatory diseases. Thus, the current study aimed at exploring the therapeutic potential of targeting ferroptosis in a polyethylene-wear-debris-induced osteolysis model. Methods: Inverted cell culture model was used for stimulating the cells with wear debris in vitro, and calvarial osteolysis model was used for evaluating the therapeutic effects of inhibitors in vivo. Results: The immunostaining of periprosthetic bone tissues demonstrated a number of osteocytes expressing ferroptosis markers. Likewise, the expressions of ferroptosis markers were confirmed in polyethylene-wear-debris-stimulated osteocyte-like cells and primary osteoblasts in a direct stimulation model but not in an indirect stimulation model. Furthermore, polyethylene wear debris was implanted onto calvarial bone and mice were treated with the ferroptosis inhibitors DFO and Fer-1. These treatments alleviated the inflammatory and pathological bone resorption induced by the wear debris implantation. Conclusions: Our data broaden the knowledge of the pathogenesis of periprosthetic osteolysis and highlight ferroptosis as a promising therapeutic target.

Introduction: Developmental dysplasia of the hip (DDH) alters joint mechanics and increases the risk of labral injury, compromising hip stability and leading to abnormal stress distribution and cartilage degeneration. However, the relationship between labral injury severity and joint loading stress in DDH remains unclear. This study investigated the effect of labral injury severity on stress distribution in DDH patients using computed tomography osteoabsorptometry (CT-OAM) and finite element analysis. Materials and methods: We analyzed 54 hips from 45 female patients undergoing joint-preserving surgery for DDH. Labral injuries were classified as simple or complicated on radial MRI. Subchondral bone density distribution was evaluated with CT-OAM, while finite element analysis of pelvic and femoral bones with cartilage was performed under a single-leg stance to assess contact pressure and area. Statistical analyses examined associations between labral injury severity and stress distribution. Results: Superior injuries showed significantly increased high-density area (HDA) in the superior acetabulum, indicating localized stress concentration (simple injury vs. complicated injury, 64.4% vs. 80.3%, p < 0.001). However, finite element analysis revealed no significant differences in contact pressure or area (simple vs. complicated, 5.3 N/mm² vs. 6.2 N/mm², p = 0.538), which we interpret as showing that bony morphology alone could not explain the observed stress patterns. Instead, the discrepancy highlights the role of labral failure reflected in CT-derived subchondral bone density. Conclusion: Complicated labral injuries, especially superiorly, were associated with localized stress accumulation in DDH.