Bone最新文献

Objective: The association between time spent in outdoor light (TOL), genetic predisposition, and the risk of osteoporosis (OP) remains unclear. This study aimed to quantify the association between TOL and OP risk, and to evaluate whether genetic predisposition modifies this relationship.

Methods: Data from the UK Biobank on 326,216 participants based on self-reported TOL, estimated bone mineral density (eBMD), and hospital inpatient records for OP diagnosis. A polygenic risk score (PRS) for OP was calculated and categorized into tertiles. We used generalized linear models, Cox proportional hazards models, and Laplace regression to evaluate the cross-sectional and longitudinal associations between TOL, PRS, and OP risk.

Results: Higher average TOL was associated with increased eBMD (β = 0.0021 g/cm², 95% CI: 0.0018-0.0024) and lower OP risk (OR = 0.9739, 95% CI: 0.8839-0.9952) in cross-sectional analysis. Participants who spent more than 3 h/day in outdoor light during summer had a reduced risk of incident OP (HR = 0.9505, 95% CI: 0.9088-0.9942) and experienced a delayed by 0.36 years (50th percentile difference = 0.3634, 95% CI: 0.0794-0.6473), compared with those exposed ≤3 h/day. Subgroup analysis indicated an additive effect of limited TOL and high genetic risk on OP susceptibility.

Conclusion: Prolonged exposure to outdoor light is associated with higher eBMD and a lower risk of developing OP, even among individuals with high genetic susceptibility. These findings suggest that increasing TOL may be a modifiable lifestyle factor to reduce OP risk, especially in genetically predisposed populations.

Denervation results in reduced bone quality, largely attributed to reduced loading due to concurrent muscle atrophy. However, sensory and sympathetic nerves also directly innervate bone, suggesting additional potential inputs into bone remodeling. A quantitative baseline of bone morphological and functional changes after nerve injury is lacking. We investigated structural, biomechanical, and immunohistochemical for time points up to three months following peripheral nerve injury. Our primary objective was to establish timelines over which bone and muscle structure and biomechanical function degraded after denervation. Additionally, we evaluated remodeling of bone innervation and vascularity and alterations in bone homeostatic markers after injury. Using a Lewis rat nerve injury model (n = 60 total rats), our findings showed rapid bone deterioration following transection of sciatic nerves of both male and female rats. Biomechanical properties of bone, including three-point bending yield force (p < 0.0001), ultimate force (p < 0.0001), and stiffness (p < 0.001), were significantly reduced as early as two weeks post-injury. At a slight delay compared to biomechanical changes, micro-CT and MRI revealed that bone mineral density (p < 0.0001) and cortical thickness (p < 0.001) also declined and porosity increased (p < 0.05) within three months. Immunohistochemical analysis revealed marked decreases in sensory (calcitonin gene related protein; CGRP) and sympathetic (Neuropeptide-Y; NPY) neuropeptides, reduced osteoblast density in periosteal regions, and increased vascular (CD-31) area fraction, accompanied by increased vascular fragmentation. These findings support the possibility that both muscle and neuronal influences underlie denervation-related bone atrophy, setting the stage for evaluation of bone health after nerve repair and targeted rehabilitative or therapeutic interventions.

Current models propose that osteogenesis occurs in regions of high mechanical stimuli such as strain, fluid velocity, or pore pressure. However, in vivo experiments on mouse tibiae subjected to cantilever loading revealed new bone formation exclusively on the anterolateral side, although the opposite posteromedial surface experienced comparable magnitudes of these stimuli. This indicates that individual stimulus magnitude is insufficient and indicate an interactive mechanism. To investigate this, a poroelastic finite element model was developed to quantify the combined effects of load-induced fluid velocity and pore pressure. Tensile loading generated negative pore pressure that stretched osteocyte processes, whereas compressive loading produced positive pore pressure that compressed them. Because fluid flow exerts drag forces that also stretch osteocytes, the combined effect of flow and negative pressure on the tensile side was hypothesized to enhance mechanotransduction and trigger osteogenesis. Four candidate stimuli were evaluated: dissipation energy density arising from (i) pore pressure, (ii) fluid velocity, (iii) their non-interactive sum, and (iv) their interaction. Comparison with in vivo data showed that only the interactive dissipation energy density accurately predicted both the spatial pattern and the average rate of new bone formation per unit bone surface under high, low, and rest-inserted cantilever loading. The model also predicted osteogenesis under axial loading, demonstrating robustness. These findings advance mechanistic understanding by establishing that the interaction between fluid velocity and pore pressure, rather than their independent effects, governs load-induced osteogenesis, and provide a predictive basis for optimizing mechanical and clinical interventions to promote bone formation and mitigate bone loss.

Telomere biology disorders (TBD) are a group of diseases that interfere with normal maintenance of telomeres, the ends of chromosomes that protect them from DNA damage. The most common manifestations are bone marrow failure, pulmonary and liver fibrosis. Systematic data on bone health in patients with TBD are scarce. Our aim was to elucidate the bone phenotype of these patients. The cohort comprises 36 adult patients (20 women and 16 men), with genetically confirmed TBD. Demographic, clinical and genetic characteristics, dual-energy X-ray absorptiometry (DXA) scans, spine X-rays and treatment details were reviewed. Median age of patients was 53.5 (43.0, 64.2) years. (Likely) pathogenic variants of the TERT gene were present in most patients. Osteopenia was diagnosed in 38.9% and osteoporosis in 25.0% of patients, 25.0% had a clinical fracture within the past 5 years, and 40.0% had at least one prevalent vertebral fracture (grade 1-3). T-score at the lumbar spine (-0.98 ± 1.48SD) was lower than at the femoral neck (-0.60 ± 1.09SD). Mean trabecular bone score (TBS) T-score was -1.32 ± 1.29SD. Bone-active therapy was used by 44.4% of the population, mostly oral bisphosphonates (85.7%). To conclude, we reported a high prevalence of osteopenia, osteoporosis, recent fractures and prevalent vertebral fractures, in patients with TBD. These results highlight the necessity of addressing the risk of osteoporosis and fractures in these patients during medical assessments. Most importantly, additionally to a DXA scan, a vertebral fracture assessment (VFA) or spine X-ray, is recommended to evaluate vertebral fractures.

Introduction/aim: Fracture risk is increased in type 1 (T1D) and type 2 diabetes (T2D). Diabetic neuropathy may contribute to this risk. We examined the association between diabetes and fracture risk, and whether diabetic neuropathy, including possible painless and possible painful neuropathy, was associated with increased risk of fracture.

Methods: In this population-based case-control study, adults (≥18 years) with and without diabetes were identified using Danish health registries. All incident fractures (excluding skull/facial) from 2019 to 2021 were included, and up to three age- and sex-matched controls were selected per case. Diabetes and diabetic neuropathy were defined by ICD and ATC codes; neuropathy was classified as possible painful or painless based on prescriptions for neuropathic pain medications. Associations between diabetes, neuropathy, and fracture risk at different sites were estimated using conditional logistic regression adjusted for confounders.

Results: We included 265,405 individuals with incident fractures and 778,466 matched controls. After multivariable adjustment, fracture risk was increased in T1D (OR 1.68, 95% CI 1.61-1.76) but not in T2D (OR 0.93, 95% CI 0.91-0.94). Diabetic neuropathy was independently associated with higher fracture risk (OR 1.47, 95% CI 1.40-1.55), with the highest risk in possible painful neuropathy (OR 1.62, 95% CI 1.50-1.74). The association between diabetic neuropathy and fracture risk appeared stronger in men and younger individuals. Site-specific analyses suggested larger point estimates for lower leg fractures and comparatively smaller estimates for vertebral, hip and lower arm fractures. The effect of neuropathy did not differ between diabetes type.

Conclusion: Diabetic neuropathy is an independent risk factor for fracture, with particularly high risk in individuals with possible painful neuropathy, potentially due to increased fall risk and impaired bone quality.

Alzheimer's disease (AD) is characterized by early-onset bone loss, yet the underlying mechanisms remain elusive. Here, we demonstrated that sympathetic hyperactivity drives vascularized osteogenesis impairment in preclinical AD through a novel PKM2-glycolysis-mediated bone vascular endothelial cell (EC) senescence pathway. Utilizing systematic transcriptome profiling complemented by in vitro functional assays and in vivo validation studies, we found that norepinephrine (NE)-induced PKM2 downregulation disrupts glycolytic flux, triggering mitochondrial dysfunction-induced senescence (MiDAS) in vascular ECs. This metabolic reprogramming of vascular ECs inhibits the differentiation of osteoprogenitors by reducing the secretion of pro-osteogenic factors. Pharmacological inhibition of β-adrenergic signaling or PKM2 activation rescues EC senescence and bone loss. Mechanistically, NE released by the sympathetic nerve suppresses c-Maf, a transcription factor critical for PKM2 expression, linking sympathetic activation to metabolic dysfunction. Furthermore, our results also showed that combination therapy with oryzanol (sympathetic modulator) and eldecalcitol (senolytic) synergistically restores vascularized osteogenesis by targeting both neurovascular and metabolic axes. These findings establish a pathogenic role for sympathetic hyperactivity in AD-related skeletal dysfunction and highlight a therapeutic strategy targeting EC senescence and glycolytic metabolism.

Periodontitis is associated with microbial lipid accumulation in gingival tissues at sites where bone destruction occurs. The primary lipid analytes identified in diseased periodontal tissues are known to be produced by Porphyromonas gingivalis (Pg), a pathogen strongly associated with periodontitis. These compounds accumulate in tissues despite clearance by gingival fibroblasts and macrophages in specific contexts. This investigation quantified lipid-dependent modulation of RANKL-mediated osteoclast formation in bone marrow macrophages and RAW 264.7 cells. The effects of Pg lipids were tested in both repeat-exposure studies, i.e. lipid priming prior to RANKL administration, and concomitant treatment with RANKL. For these studies, we used RANKL concentrations that mirror concentrations measured at disease sites. Osteoclast formation was evaluated by quantifying TRAP-positive cells. Our findings show that RANKL-induced osteoclast formation from bone marrow macrophages and RAW cells is enhanced, particularly in cells primed with lipids prior to RANKL administration. These results show a 2- to 10-fold increased in numbers of osteoclasts formed in cultures pre-exposed to Pg lipids with significance levels often at p < 0.0001. Enhanced osteoclast formation occurs despite loss of TNF-α secretory responses after repeated lipid exposure. These results indicate that RANKL at levels observed in periodontitis gingival tissues will promote osteoclast formation when bacterial lipids are also present. This suggests that lipid deposition could be used to identify at-risk sites for bone destruction in periodontitis. Collectively, our data support the notion that osteoclast formation is enhanced by the site-specific deposition of Pg lipids which contribute to localized bone loss around teeth in human periodontitis.

Purpose: Paget's disease of bone (PDB) is the second most common metabolic bone disorder. We aimed to characterize the clinical and demographic profile of a Portuguese PDB cohort, identify factors associated with polyostotic disease, and compare retreatment needs between patients treated with zoledronate or alternative first-line therapies.

Methods: Retrospective, longitudinal, single-centre cohort study. Demographic and clinical data were collected. Associations with polyostotic disease were assessed using parametric and non-parametric tests and multivariable logistic regression. Drug survival was analysed with Kaplan-Meier analysis, and retreatment rates compared using log-rank test and Cox regression.

Results: Eighty patients diagnosed between 1974 and 2021 were included; 58.8% were female and age at diagnosis was 63.0 ± 12.2 years. Most patients (72.5%) were born in rural areas, with clustering in Alentejo. Forty-one patients (51.2%) had polyostotic PDB. Vertebrae, femur, pelvis, sacrum and skull involvement were associated with polyostotic disease. Seventeen patients (22.1%) required retreatment. Mean first-line drug survival with zoledronate was 16.0 years (95% CI 14.3-17.6) compared to 11.7 years (95% CI 4.9-18.4) with other drugs. Drug survival was significantly lower with non-zoledronate therapy, with higher retreatment rates (crude HR 9.49 [95% CI 3.28-27.44]; log-rank p < 0.001), even after adjustment (adjusted HR 10.10 [95% CI 2.12-48.0]; p = 0.004).

Conclusion: This study, the largest Portuguese PDB cohort, highlights a predominance in rural areas, identifies skeletal sites linked to polyostotic disease, and shows zoledronate is associated with significantly lower retreatment rates.

The ketogenic diet (KD) is an established treatment for intractable epilepsy in children. KD has also become increasingly popular for weight loss, and it has shown therapeutic potential for treating neurodegenerative diseases. However, KD causes bone loss in epileptic children, and its effects on the adult skeleton are unknown. In the current study, we investigated the effect of KD on bone at different ages using growing (4-week-old) and adult (14-week-old) male C57BL/6 J mice. We also examined if KD-induced bone loss could be recovered via exercise. We hypothesized that KD would cause bone loss at all ages, the rate of bone loss would depend on age, and that KD alters osteoblast, osteoclast, and osteocyte activity. We also predicted KD would reduce the anabolic effects of exercise. We quantified bone density in-vivo and conducted ex-vivo analysis of bone microstructure and strength, osteoblast and osteoclast activity, and osteocyte lacunar size. KD induced bone loss was evident after 4 weeks in growing animals and after 8 weeks in adult mice. Analysis of serum showed that KD caused declines in bone formation markers, and measurement of osteocyte lacunar dimensions via x-ray microscopy showed increases in lacunar volume, but osteoclasts were unaffected. KD also reduced the magnitude of exercise induced changes in cortical bone mechanical properties. These findings suggest that KD-initiated bone loss is not a clinical problem limited to children, and it may be a significant risk factor for osteoporotic fracture in adults.

Fractures are common musculoskeletal injuries associated with severe pain, and effective analgesia is essential for fracture management. Current therapies such as NSAIDs and opioids have significant limitations, driving interest in alternative analgesics, an avenue where cannabinoids hold great promise. While cannabinoids are increasingly promoted for various indications, robust scientific evidence supporting their use remains limited. We previously demonstrated that cannabidiol (CBD) and cannabigerol (CBG), two non-psychoactive cannabinoids, alleviate fracture pain and promote bone repair. Cannabichromene (CBC), another non-psychoactive cannabinoid, has shown analgesic effects in different disease models, but its impact on fracture pain and healing is unknown. Using a murine tibial fracture model, we investigated CBC's effects on pain and bone healing. CBC significantly reduced fracture pain, improving mechanical and cold allodynia, thermal hyperalgesia, and gait function. However, bone healing was impaired, with delayed soft-callus resorption, increased bone cell apoptosis, elevated osteoclast activity, and reduced bone formation and mineralization. In vitro, CBC promoted osteoclastogenesis, supporting its resorptive effect. These findings contrast with the reported benefits of CBD and CBG on fracture repair, highlighting that not all cannabinoids are suitable for fracture management. Individual compounds must be carefully evaluated to balance analgesia with bone healing. Caution is warranted when using medical cannabis or cannabinoid oils with variable compositions, as their effects on healing are unpredictable. The divergent effects of CBD and CBG versus CBC may also guide future structure-activity relationship studies for designing synthetic cannabinoids to promote fracture healing.