With increases in life expectancy, the number of patients requiring joint replacement therapy and experiencing periprosthetic osteolysis, the most common complication leading to implant failure, is growing or underestimated. In this study, we found that osteolysis progression and osteoclast differentiation in the surface of the skull bone of adult mice were accompanied by significant expansion of lymphatic vessels within bones. Using recombinant VEGF-C protein to activate VEGFR3 and promote proliferation of lymphatic vessels in bone, we counteracted excessive differentiation of osteoclasts and osteolysis caused by titanium alloy particles or inflammatory cytokines LPS/TNF-α. However, this effect was not observed in aged mice because adipogenically differentiated mesenchymal stem cells (MSCs) inhibited the response of lymphatic endothelial cells to agonist proteins. The addition of the JAK inhibitor ruxolitinib restored the response of lymphatic vessels to external stimuli in aged mice to protect against osteolysis progression. These findings suggest that inhibiting SASP secretion by adipogenically differentiated MSCs while activating lymphatic vessels in bone offers a new method to prevent periprosthetic osteolysis during joint replacement follow-up.

To alleviate bone loss, most current drugs target osteoclasts. Saikosaponin A (Ssa), a triterpene saponin derived from Bupleurum falcatum (also known as Radix bupleuri), has immunoregulatory, neuromodulatory, antiviral, anticancer, anti-convulsant, anti-inflammatory, and anti-proliferative effects. Recently, modulation of bone homeostasis was shown to involve ferroptosis. Herein, we aimed to determine Ssa\'s inhibitory effects on osteoclastogenesis and differentiation, whether ferroptosis is involved, and the underlying mechanisms. Tartrate-resistant acid phosphatase (TRAP) staining, F-actin staining, and pit formation assays were conducted to confirm Ssa-mediated inhibition of RANKL-induced osteoclastogenesis in vitro. Ssa could promote osteoclast ferroptosis and increase mitochondrial damage by promoting lipid peroxidation, as measured by iron quantification, FerroOrange staining, Dichloro-dihydro-fluorescein diacetate, MitoSOX, malondialdehyde, glutathione, and boron-dipyrromethene 581/591 C11 assays. Pathway analysis showed that Ssa can promote osteoclasts ferroptosis by inhibiting the Nrf2/SCL7A11/GPX4 axis. Notably, we found that the ferroptosis inhibitor ferrostatin-1 and the Nrf2 activator tert-Butylhydroquinone reversed the inhibitory effects of Ssa on RANKL-induced osteoclastogenesis. In vivo, micro-computed tomography, hematoxylin and eosin staining, TRAP staining, enzyme-linked immunosorbent assays, and immunofluorescence confirmed that in rats with periodontitis induced by lipopolysaccharide, treatment with Ssa reduced alveolar bone resorption dose-dependently. The results suggested Ssa as a promising drug to treat osteolytic diseases.

UNASSIGNED: Periprosthetic osteolysis is a prevalent complication following total ankle arthroplasty (TAA), implicating various cytokines in osteoclastogenesis as pivotal in this process. This study aimed to evaluate the relationship between osteolysis and the concentrations of osteoclastogenesis-related cytokines in synovial fluid and investigate its clinical value following TAA.
UNASSIGNED: Synovial fluid samples from 23 ankles that underwent revision surgery for osteolysis following TAA were analyzed as the osteolysis group. As a control group, we included synovial fluid samples obtained from 23 ankles during primary TAA for osteoarthritis. The receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) ratio in these samples was quantified using sandwich enzyme-linked immunosorbent assay techniques, and a bead-based multiplex immunoassay facilitated the detection of specific osteoclastogenesis-related cytokines.
UNASSIGNED: RANKL levels averaged 487.9 pg/mL in 14 of 23 patients in the osteolysis group, with no detection in the control group\'s synovial fluid. Conversely, a significant reduction in OPG levels was observed in the osteolysis group (p = 0.002), resulting in a markedly higher mean RANKL/OPG ratio (0.23) relative to controls (p = 0.020). Moreover, the osteolysis group had increased concentrations of various osteoclastogenesis-related cytokines (tumor necrosis factor-α, interleukin [IL]-1β, IL-6, IL-8, IP-10, and monocyte chemotactic protein-1) in the synovial fluid relative to the control group.
UNASSIGNED: Our results demonstrated that periprosthetic osteolysis was associated with osteoclastogenesis activation through an elevated RANKL/OPG ratio following TAA. We assume that RANKL and other osteoclastogenesis-related cytokines in the synovial fluid have clinical value as a potential marker for the development and progression of osteolysis following TAA.

Introduction Surgery is the recommended treatment for medication-related osteonecrosis of the jaw (MRONJ). However, the disease may recur postoperatively. We reviewed imaging findings in patients undergoing three or more surgeries. Patients and methods One hundred fifty patients with MRONJ underwent surgery at our hospital. Here, we present the characteristics of 34 surgeries in nine patients (two men and seven women; mean age, 73.9 years) who underwent surgery at least three times. Results Three and six patients had maxillary and mandibular lesions, respectively. The primary disease was malignancy in eight patients, and denosumab was used in seven patients. All patients initially underwent either partial maxillectomy or marginal mandibulectomy, and segmental mandibulectomy was not performed. The number of surgeries ranged from three to six (average, 3.8). Healing was eventually achieved in seven cases, but not in two cases. Of the 27 unsuccessful surgeries, postoperative cone-beam computed tomography revealed no residual osteolysis, periosteal reaction, or osteosclerosis after seven surgeries and some residual lesions after 19 surgeries; imaging was not performed after one surgery. In contrast, among the seven successful surgeries, no residual osteolysis, periosteal reaction, or osteosclerosis was observed in all six cases in which postoperative computed tomography was performed. Conclusion Recurrence is more common in patients with residual areas of osteolysis, periosteal reactions, or mixed-type osteosclerosis, and including these areas in the resection is desirable.

UNASSIGNED: The Latarjet procedure was developed for the treatment of anterior shoulder instability in young, high-demand patients with attritional glenoid bone loss, whose risk of redislocation following primary dislocation may exceed 90%. Coracoid graft osteolysis and prominent screws are commonly observed in late computed tomography (CT) scans of patients who re-present following the procedure, but the clinical relevance of osteolysis in the overall Latarjet cohort is undetermined. We aimed to evaluate clinical and radiological outcomes in patients who underwent the Latarjet procedure, and to determine if severe coracoid graft osteolysis compromised clinical outcomes.
UNASSIGNED: This was a retrospective analysis of patients who underwent the open Latarjet procedure. Patients were invited via an e-questionnaire that contained a Western Ontario Shoulder Instability Index (WOSI), and queried about redislocation and reoperation since index surgery. Preoperative glenoid bone loss was calculated on CT using the best-fit circle method. Osteolysis was graded (0, screw head buried in graft; 1, screw head exposed; 2, threads exposed; 3, complete resorption/severe osteolysis) at the level of the proximal and distal screws respectively, on axial CT scans performed ≥ 12 months postoperatively.
UNASSIGNED: Between 2011 and 2022, a single surgeon performed 442 Latarjet procedures. One hundred fifty eight patients responded to the questionnaire at median (interquartile range [IQR]) 44 (27-70) months postoperatively, among whom the median (IQR) WOSI score was 352 (142-666) points (0 = best, 2100 = worst). Recurrent anterior instability occurred in 3/158 (2%) patients. One patient required reoperation for this indication. Among patients who had CT scans ≥ 12 months postoperatively (median [IQR] 40 [29-69] months), 1 patient developed severe osteolysis around both screws (WOSI = 90), 17/62 (27%) patients developed severe osteolysis around 1 screw, all of which were proximal (median [IQR] WOSI = 235 [135-644]), and 44/62 (71%) patients did not develop severe osteolysis around either screw (median [IQR] WOSI = 487 [177-815]). There were no statistically significant differences in WOSI scores between groups based on the presence of severe osteolysis.
UNASSIGNED: The Latarjet is reliable procedure that has a low rate of redislocation and reoperation. Severe coracoid graft osteolysis occurs with time, and always affects the proximal graft first. The presence of severe osteolysis did not compromise clinical outcomes.

Progressive osteolysis can occur at the cement-bone interface of joint replacements and the associated loss of fixation can lead to clinical loosening. We previously developed a rat hemiarthroplasty model that exhibited progressive loss of fixation with the development of cement-bone gaps under the tibial tray that mimicked patterns found in human arthroplasty retrievals. Here we explored the ability of a bisphosphonate (zoledronic acid, ZA) to attenuate cement-bone osteolysis and maintain implant stability. Sprague-Dawley rats (n = 59) received a poly(methylmethacrylate) cemented tibial component and were followed for up to 12 weeks. Treatment groups included peri-operative administration of ZA (ZA group), administration of ZA at 6 weeks postop (late ZA group), or vehicle (Veh group). There was a 60% reduction in the rate of cement-bone gap formation for the ZA group (0.15 mm3/week) compared to Veh group (0.38 mm3/week, p = 0.016). Late ZA prevented further progression of gap formation but did not reverse bone loss to the level achieved in the ZA group. Micromotion from five times body weight toggle loading was positively correlated with cement-bone gap volume (p = 0.009) and negatively correlated with the amount of cement in the metaphysis (p = 0.005). Reduced new bone formation and enduring nonviable bone in the epiphysis for the ZA group were found. This suggests that low bone turnover in the epiphysis may suppress the early catabolic response due to implantation, thereby maintaining better fixation in the epiphysis. This preclinical model presents compelling supporting data documenting improved maintenance of the cement-bone fixation with the use of peri-operative bisphosphonates.

OBJECTIVE: Cervical total disc replacement (cTDR) has been established as an alternative treatment for degenerative cervical radiculopathy and myelopathy. While the rate of complications for cTDR is reasonably low, recent studies have focused on bone loss after cTDR. The purpose of this work is to develop a clinical management plan for cTDR patients with evidence of bone loss. To guide our recommendations, we undertook a review of the literature and aimed to determine: (1) how bone loss was identified/imaged, (2) whether pre- or intraoperative assessments of infection or histology were performed, and (3) what decision-making and revision strategies were employed.
METHODS: We performed a search of the literature according to PRISMA guidelines. Included studies reported the clinical performance of cTDR and identified instances of cervical bone loss.
RESULTS: Eleven case studies and 20 cohort studies were reviewed, representing 2073 patients with 821 reported cases of bone loss. Bone loss was typically identified on radiographs during routine follow-up or by computed tomography (CT) for patients presenting with symptoms. Assessments of infection as well as histological and/or explant assessment were sporadically reported. Across all reviewed studies, multiple mechanisms of bone loss were suspected, and severity and progression varied greatly. Many patients were reportedly asymptomatic, but others experienced symptoms like progressive pain and paresthesia.
CONCLUSIONS: Our findings demonstrate a critical gap in the literature regarding the optimal management of patients with bone loss following cTDR, and treatment recommendations based on our review are impractical given the limited amount and quality evidence available. However, based on the authors\' extensive clinical experience, close follow-up of specific radiographic observations and serial radiographs to assess the progression/severity of bone loss and implant changes are recommended. CT findings can be used for clinical decision-making and further follow-up care. The pattern and rate of progression of bone loss, in concert with patient symptomatology, should determine whether non-operative or surgical intervention is indicated. Future studies involving implant retrieval, histopathological, and microbiological analysis for patients undergoing cTDR revision for bone loss are needed.

Lung cancer stands as a major contributor to cancer-related fatalities globally, with cigarette smoke playing a pivotal role in its development and metastasis. Cigarette smoke is also recognized as a risk factor for bone loss disorders like osteoporosis. However, the association between cigarette smoke and another bone loss disorder, lung cancer osteolytic bone metastasis, remains largely uncertain. Our Gene Set Enrichment Analysis (GSEA) indicated that smokers among lung cancer patients exhibited higher expression levels of bone turnover gene sets. Both The Cancer Genome Atlas (TCGA) database and our clinic samples demonstrated elevated expression of the osteolytic factor IL-6 in ever-smokers with bone metastasis among lung cancer patients. Our cellular experiments revealed that benzo[α]pyrene (B[α]P) and cigarette smoke extract (CSE) promoted IL-6 production and cell migration in lung cancer. Activation of the PI3K, Akt, and NF-κB signaling pathways was involved in cigarette smoke-augmented IL-6-dependent migration. Additionally, cigarette smoke lung cancer-secreted IL-6 promoted osteoclast formation. Importantly, blocking IL-6 abolished cigarette smoke-facilitated lung cancer osteolytic bone metastasis in vivo. Our findings provide evidence that cigarette smoke is a risk factor for osteolytic bone metastasis. Thus, inhibiting IL-6 may be a valuable therapeutic strategy for managing osteolytic bone metastasis in lung cancer patients who smoke.

BACKGROUND: There is a paucity of data beyond 15 years on the survivorship of total hip arthroplasty since the introduction of highly cross-linked polyethylene (HXLPE) liners. Our aim was to evaluate implant survivorship, liner wear rates, and clinical outcomes after primary total hip arthroplasty using HXLPE liners implanted between 1999 and 2002.
METHODS: Between 1999 and 2002, 690 primary total hip arthroplasties utilizing 28-mm femoral heads and HXLPE liners of a single design were identified using our institutional total joint registry. Femoral heads were made of metal in 96% of cases and ceramic in 4%. The mean age was 56 years, 48% were women, and the mean body mass index was 30. Survivorship analyses were performed for the outcomes of implant revision, reoperation, and complications for the entire cohort. Linear HXLPE liner wear rates were determined on 197 hips with radiographs with more than 18.5 years of follow-up.
RESULTS: At 20 years, survivorship free of revision was 94%, free of reoperation was 92%, and free of any complication was 81%. There were no documented wear-related revisions. The linear wear rate at a mean of 20.3 years postoperatively was 0.02 mm/y. There was no statistically significant difference in measured wear observed between the first available postoperative radiographs and those taken at the final follow-up. The use of elevated liners, patient body mass index, age, preoperative diagnosis, acetabular component inclination, and anteversion angles were not associated with increased wear rates. Mean Harris hip scores improved from 52 preoperatively to 90 at greater than 18.5 years CONCLUSIONS: Primary total hip arthroplasties using a single first-generation HXLPE liner demonstrated excellent survivorship and clinical outcomes at long-term follow-up with no wear-related revisions. Wear rates of HXLPE liners at 20 years are exceedingly low and are not significantly impacted by acetabular component position or patient-dependent variables such as BMI.
METHODS: IV.

UNASSIGNED: Over-activated osteoclast (OC) is a major cause of diseases related to bone loss and bone metabolism. Both bone resorption inhibition and apoptosis induction of osteoclast are crucial in treating these diseases. X-linked inhibitor of apoptosis protein (XIAP)-associated factor 1 (XAF1) is an important interferon-stimulated and apoptotic gene. However, how XAF1 regulates bone formation and remodeling is unknown.
UNASSIGNED: We generate global and chimeric Xaf1 knockout mouse models and utilize these models to explore the function and mechanism of XAF1 in regulating bone formation and remodeling in vivo and in vitro.
UNASSIGNED: We show that XAF1 depletion enhances osteoclast generation in vitro. XAF1 knockout increases osteoclast number and bone resorption, thereby exacerbating bone loss in both OVX and osteolysis models. Activation of XAF1 with BV6 (a potent XIAP inhibitor) suppresses osteoclast formation. Mechanistically, XAF1 deletion decreases osteoclast apoptosis by facilitating the interaction between XIAP and caspase-3/7.
UNASSIGNED: Our data illustrates an essential role of XAF1 in controlling osteoclastogenesis in both osteoporosis and osteolysis mouse models and highlights its underlying mechanism, indicating a potential role in clinical treatment.The translational potential of this article: The translation potential of this article is that we first indicated that osteoclast apoptosis induced by XAF1 contribute to the progression of osteoporosis and osteolysis, which provides a novel strategy in the prevention of osteoporosis and osteolysis.