Abstract Fragility fracture is a major cause of chronic disease morbidity leading to reduced life quality and quantity in middle-aged and older women. Many risk factors have been identified but the relative contribution of each of them when being considered simultaneously remains unclear. We conducted a secondary analysis using data from a large Canadian prospective cohort study to investigate, among all the known risk factors, which are statistically independently associated with a first incident fragility fracture in middle-aged and older women after mutual adjustment. A total of 10,930 female participants with a mean age of 61.70 ± SD 10.00 years old were included in the analytical sample. 1048 fracture events were self reported during the six-year follow-up. Multivariate logistic regression considering only variables feasible to obtain during a single primary care visit revealed that eight factors were associated with increased fracture risk and were robust across all analyses including adjustment for bone mineral density T-score total hip and after multiple imputation for missing data. These factors are currently taking antidepressants [OR 1.29 (1.18, 1.42), p=.0060], impaired balance [OR 1.34 (1.21, 1.49), p=.0041], epilepsy [OR 2.18 (1.66, 2.87), p=.0043], lower hand grip strength [OR 0.97 (0.96, 0.98) per kg, p<.0001], greater height [OR 1.03 (1.02, 1.03) per cm, p<.0001], osteoarthritis [OR 1.19 (1.10, 1.29), p=.0234], parental hip fracture after age 50 [OR 1.30 (1.18, 1.43), p=.0068] and a personal history of fall in the past 12 months [OR 1.78 (1.61, 1.96), p<.0001]. These findings suggest that middle-aged and older women with such factors may be at higher risk of sustaining fracture in near future and could benefit from clinical attention and targeted preventive strategies.
Osteogenesis imperfecta (OI) is a collagen-related disorder characterized by frequent fractures. Sclerostin neutralizing antibodies (Scl-Ab) have been shown to increase bone mass in mouse models and adults with OI. However, serum concentrations of the WNT antagonist dickkopf-1 (DKK1) are elevated in people with OI and expression of both Sost and Dkk-1 are elevated in mice after Scl-Ab treatment, potentially dampening the therapeutic response. We aimed to evaluate the effect of rodent bispecific antibody (rbsAb) against DKK1 and sclerostin in a mouse model of dominant OI with a Col1a1 structural defect. Ten-week-old male and female Brtl/+ and WT mice received twice weekly injections of rbsAb or vehicle for 8 weeks. Assessment of femoral bone microstructure and density using in vivo microCT showed rbsAb treatment led to greater percent change from baseline in all cortical and trabecular bone mass and microstructural parameters compared to vehicle in all groups (eg. Ct.Th in Brtl/+ males rbsAB: 52%, vehicle: 2%; females rbsAB: 55%, vehicle: 10%). MicroCT-based timelapse morphometry revealed that rbsAb led to greater bone formation and lower bone resorption on endocortical, periosteal, and trabecular surfaces. Fluorochrome-based histomorphometry primarily showed greater mineralizing surfaces with rbsAb treatment. rbsAb treated mice had greater bone strength and stiffness and there was no treatment-related difference in post-yield displacement. MicroCT analysis of L4 vertebrae revealed greater bone mass in all groups with rbsAb treatment compared to vehicle. The percent change from baseline in serum bone formation marker P1NP was greater after 4 weeks of treatment compared to vehicle in all groups, but only in females at 8 weeks; no treatment-related difference was measured in resorption marker TRAcP5b. rbsAb treatment led to greater Dkk-1 and Sost gene expression compared to vehicle in all groups. This data demonstrates rbsAb treatment elicited a potent anabolic response in both WT and Brtl/+ mice.
Abstract Menarche marks the onset of high estrogen exposure, yet the relationship between age at menarche (AAM) and osteoporosis is not fully understood. This study aimed to investigate the associations of AAM with bone mineral density (BMD), osteoporosis, and fractures across different age decades. In this cross-sectional study using data from the China Osteoporosis Prevalence Study (COPS), we examined the correlations between AAM and BMD at the femoral neck (FN), total hip (TH), and lumbar spine (LS) in women aged 20-29 to ≥70 years. Peak bone mass was determined based on BMD trends across age groups. Among postmenopausal women, we also assessed the associations of AAM with osteoporosis, vertebral fractures, and clinical fractures within the past five years. This cross-sectional analysis is exploratory and intended to generate hypotheses about the life-course association between AAM and bone health. Later AAM was associated with a a cross-sectional pattern of peak bone mass estimates occurring in older age groups at the FN and TH; however, no significant difference in peak bone mass magnitude was observed between AAM groups. In postmenopausal women, later AAM correlated with lower BMD at the LS and TH, and higher odds of osteoporosis. No significant association with fractures was observed. Later AAM was associated with estimates of peak bone mass timing at older age groups at the FN and TH without altering its magnitude. In postmenopausal women, later AAM was associated with modestly lower LS and TH BMD and higher odds of osteoporosis. Therefore, earlier osteoporosis screening is warranted for these women after menopause, and BMD assessment should include sites beyond the femoral neck.
Abstract Posttraumatic lymphedema is a frequent yet underrecognized complication of severe limb trauma and fractures. Although chronic inflammation is known to impair bone repair, it is entirely unknown whether lymphatic dysfunction itself affects skeletal regeneration. To date, no clinical or experimental data exist that directly link lymphedema to impaired bone healing. Using a validated rat model including both male and female animals, tibial bone defects were created with or without concomitant lymphatic vessel disruption. Bone regeneration was assessed by histology (aniline blue), Osteocalcin immunohistochemistry, and high-resolution micro-computed tomography (μCT). Mechanistic analyses included markers of osteoblast differentiation (RUNX2), remodeling-associated signaling (RANKL), endothelial/angiogenesis-associated signaling (PECAM-1), and cellular proliferation (PCNA), and multiplex Luminex-based cytokine and chemokine profiling. Posttraumatic lymphedema significantly impaired bone regeneration, evidenced by reduced osteoid formation, diminished Osteocalcin expression, and lower bone volume fraction on μCT (p = 0.0246). The PTL phenotype was associated with reduced osteoblast differentiation (RUNX2↓, p = 0.0038), reduced RANKL expression, consistent with altered remodeling-associated signaling (p = 0.0002), and decreased PECAM-1 expression (p = 0.0026), while PCNA expression remained unchanged. Luminex analysis revealed a distinct proinflammatory and chemotactic signature characterized by elevated TNF-α, IL-6, IL-12p70, MIP-1α, RANTES, MCP-1, and MIP-2.. This cytokine and chemokine upregulation occurred in both lymphedema groups – regardless of whether a bone defect was present – whereas animals with isolated bone defects showed only minimal inflammatory activation. This study provides experimental evidence that posttraumatic lymphedema is associated with impaired bone regeneration. The PTL phenotype was accompanied by a sustained proinflammatory and chemotactic microenvironment, reduced osteoblast differentiation, altered remodeling-associated signaling, and reduced PECAM-1 expression. These findings identify a previously unrecognized association between posttraumatic lymphatic dysfunction and skeletal repair and provide a basis for further mechanistic investigation.
Abstract Hip fracture risk depends on both skeletal fragility and the mechanics of a fall, yet current clinical assessment focuses primarily on bone density. We compared femoral neck areal bone mineral density (aBMD: DXA-derived in Emilia-Romagna and CT-derived in KURE), finite element model (FEM)-based femoral strength (S), and biofidelic FEM-based probability of hip fracture (PFx) for identifying individuals at risk of hip fracture. Predictors were evaluated in the Emilia-Romagna cohort (n = 53 women), classified by hip fracture status at assessment, and the Korean Urban Rural Elderly (KURE) cohort (n = 125), followed prospectively for incident hip fracture. In Emilia-Romagna, PFx showed discrimination for fracture status (AUC 0.77, 95% CI 0.63–0.89) comparable to aBMD and S. In KURE, each 1-SD decrease in aBMD and S was associated with increased fracture risk (hazard ratio (HR) 2.54, p = 0.047; HR 5.96, p = 0.015), while each 1-SD increase in PFx showed a comparable association (HR 5.70, p < 0.001); after adjustment for age, sex, and BMI, S and PFx remained significant independent predictors, while aBMD did not. Tertile-based risk stratification identified significantly different fracture incidence for the highest versus lowest tertile of S (HR 0.10, p = 0.037) and PFx (HR 16.04, p = 0.009), but not aBMD (p = 0.158). Adjusted PFx showed a higher C-index (0.900) than the clinical model of age, sex, and BMI (0.802). These findings indicate that PFx may capture the clinically relevant determinants of fracture risk and support further evaluation of biofidelic FEM for personalized hip fracture risk assessment.
