BACKGROUND Osteoporosis is the result of an imbalance between bone resorption and bone formation. Osthole is a coumarin compound derived from medicinal plants that exerts a significant osteoprotective effect, however, its precise molecular mechanism has not yet been fully elucidated. AIM To investigate whether osthole activates the estrogen receptor (ER), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK), and Wnt/β-catenin pathways in osteoblasts, thereby indirectly suppressing osteoclastogenesis via osteoblast-derived signals. METHODS Molecular docking was used to predict osthole-target binding. The proliferation, differentiation, and mineralisation of osteoblasts (MG-63, primary rat osteoblasts, and MC3T3-E1) were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and alkaline phosphatase activity, and Alizarin Red staining. Flow cytometry was used to measure apoptosis. Reverse transcription-quantitative polymerase chain reaction and western blot were performed to analyse the expression of osteoprotegerin, receptor activator of nuclear factor-κB ligand (RANKL), Osterix, and pathway molecules (phosphorylated ERK, phosphorylated AKT, and β-catenin). enzyme-linked immunosorbent assay was used to quantify RANKL. Conditioned medium from osthole-treated MC3T3-E1 cells was applied to RAW264.7 cells. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, tartrate-resistant acid phosphatase staining/activity, and reverse transcription-quantitative polymerase chain reaction were used to evaluate osteoclast viability, differentiation, and gene expression. Specific inhibitors (fulvestrant 182780, wortmannin, PD98059 and dickkopf-1) were used to verify pathway involvement. RESULTS Docking results predicted that osthole binds to the active pockets of ERα, AKT, and ERK with high binding affinity, suggesting potential interactions. Osthole promoted the proliferation, differentiation, and mineralisation of MG-63, rat osteoblast, and MC3T3-E1 cells in a concentration-dependent manner, and inhibited cisplatin-induced apoptosis of MG-63 cells. Additionally, osthole was found to upregulate osteoprotegerin and Osterix expression, downregulate RANKL expression, and activate the ER, PI3K/AKT, MEK/ERK, and Wnt/β-catenin signaling pathways in osteoblasts. Conditioned medium from osthole-treated MC3T3-E1 cells inhibited the viability, differentiation, and expression of osteoclast-specific genes (TRAP , CTR , RANK , CatK and MMP-9 ) in RAW264.7 cells. The osteoprotective effects of osthole were reversed by specific pathway inhibitors. CONCLUSION Osthole exerts osteoprotective effects by promoting the function of osteoblasts and indirectly suppressing osteoclastogenesis in an osteoblast-dependent manner. This process primarily occurs through the activation of the ER, PI3K/AKT, MEK/ERK, and Wnt/β-catenin signalling pathways in osteoblasts.
BACKGROUND The populations undergoing total joint arthroplasty (TJA) and those receiving hormone replacement therapy (HRT) overlap considerably, as both predominantly comprise older adults. HRT includes estrogen RT (ERT) and testosterone RT (TRT). Whether these hormonal interventions influence postoperative medical complications (e.g. , thromboembolism, acute kidney injury, cardiac events) or implant-related outcomes (e.g. , infection, loosening, revision) remains uncertain. Existing studies provide conflicting results, and a direct comparison between ERT and TRT is lacking. AIM To systematically compare the associations of ERT and TRT with complications following TJA. METHODS PubMed, EMBASE, Web of Science, and Cochrane Library were searched through April 2026. Two reviewers independently screened studies, extracted data, and assessed bias. We examined medical complications, including venous thromboembolism (VTE), acute kidney injury (AKI), cardiac events, pneumonia, sepsis, blood transfusion, together with implant-related outcomes, including revision surgery, periprosthetic joint infection (PJI), periprosthetic fracture, and mechanical loosening. A narrative synthesis was performed due to design and clinical heterogeneity. The review followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and was registered (PROSPERO: CRD420261366259). RESULTS A total of 15 studies met the inclusion criteria; 11 reported medical complications and 13 reported implant-related outcomes. ERT yielded mixed, procedure-specific results: Certain total knee arthroplasty (TKA) cohorts had reduced risks of deep vein thrombosis and blood transfusion, while others demonstrated elevated risks of TKA cardiac complications, total hip arthroplasty (THA) mechanical loosening, and total shoulder arthroplasty revision. By contrast, TRT showed a more consistent association with increased risks of PJI, AKI, and revision surgery, although several cohorts found no significant association with VTE after THA, periprosthetic fracture, or blood transfusion. CONCLUSION Evidence suggests inconsistent perioperative associations for ERT in TJA, whereas TRT may be linked to higher odds of PJI and AKI. However, heterogeneity and observational design limitations preclude causal inference, thus requiring prospective studies.
BACKGROUND Chronic lateral ankle instability may coexist with occult syndesmotic injury despite the absence of definite distal tibiofibular diastasis on static imaging. Because symptoms may overlap with those of isolated lateral ankle instability, this condition can remain unrecognized. This study hypothesized that selected patients with persistent anterior syndesmotic symptoms and stress-confirmed occult syndesmotic instability would demonstrate sustained improvement after combined Broström repair and suture-button stabilization. AIM To evaluate 5-year clinical outcomes of combined Broström repair and suture-button stabilization in this selected cohort. METHODS This uncontrolled retrospective case series at a tertiary hospital included 16 of 1487 patients treated from April 2018 to May 2021. Eligibility required chronic lateral ankle instability, focal syndesmotic symptoms, no static diastasis, failed conservative treatment, and qualitative confirmation by three intraoperative stress tests. No comparator or quantitative diagnostic threshold was used. All underwent combined Broström repair and suture-button stabilization. Repeated outcomes were analyzed using Friedman and Bonferroni-adjusted exact Wilcoxon tests. RESULTS The median injury-to-surgery interval was 21.0 months (interquartile range, 8.25-120.0 months). Preoperative visual analogue scale, American Orthopaedic Foot and Ankle Society, Foot and Ankle Ability Measure, and Karlsson scores were 3.00 ± 1.32, 69.69 ± 12.11, 69.67 ± 12.15, and 64.00 ± 11.86, respectively. At 5 years, scores were 0.44 ± 0.63, 92.06 ± 6.89, 89.21 ± 10.19, and 88.12 ± 8.69 (all adjusted P < 0.001; paired Cohen’s d z, -2.03, 2.06, 1.94, and 2.40). All patients returned to work at 2.44 ± 0.68 months. Seven patients (43.8%) underwent button removal at 1 year; none had implant-related symptoms at 5 years. CONCLUSION In this uncontrolled case series, combined treatment was associated with improvement, but the findings are exploratory and do not establish the independent benefit of suture-button stabilization.
Anterior knee pain is a well-recongized, multifactorial issue after anterior cruciate ligament reconstruction using bone-patellar tendon-bone autograft. We appreciate the comprehensive commentary by Olaran and Garcia-Mansilla on our recently published study “Anterior knee pain in anterior cruciate ligament -reconstruction using bone-patellar tendon -bone graft and autologous bone grafting”. In this reply, we acknowledge the limitations of our retrospective, single-center study and emphasize the need for larger prospective randomized trials. We also clarify key technical aspects of our approach, including meticulous graft harvest, autologous bone grafting of patellar and tibial donor-site defects using cancellous bone obtained during tunnel drilling and avoidance of soft-tissue and cartilage injury. These refinements have helped in reduction of donor-site morbidity and anterior knee pain after bone-patellar tendon-bone anterior cruciate ligament-reconstruction in our patient cohort. However, these descriptive findings in a retrospective study are hypothesis-generating and cannot establish definitive preventive efficacy. Prospective randomized trials are required to evaluate the independent impact of these surgical refinements on donor-site morbidity.
