Journal of Bone and Mineral Research最新文献

Three-dimensional modeling of hip DXA scans has been proposed to partition BMD into cortical surface (csBMD) and trabecular "volumetric" (tvBMD). We assessed in a population-based cohort, whether such partitioning contributes to fracture risk assessment compared to aBMD alone. Participants (N = 4908) from the Rotterdam Study comprised 56% women, with a mean age of 67.4 (SD = 10.1) years. Hip DXA scans were analyzed with enCore (GE Lunar) and 3D-Shaper software. Pearson partial correlation was calculated between aBMD, csBMD, and tvBMD at the total hip, femoral neck, and trochanter. Incident fractures were collected from GP or hospital records. During a mean follow-up of 6.8 (SD = 2.5) years, 171 sustained a hip fracture, and 1019 any-type fractures. Fracture risk estimates were determined as hazard ratios (HR) per SD decrease in BMD, from Cox-regression adjusted for multiple confounders. High correlation (r = >.81; p < .001) was observed between aBMD and the modeled 3D parameters, and between csBMD and tvBMD (r = 0.85; p < .001 at the total hip). Lower aBMD was associated with higher incidence of any-type (HR = 1.60, 95% CI: 1.43-1.78) and hip (HR = 2.46, 95% CI: 1.90-3.17) fracture; lower csBMD with increased risk of any-type (HR = 1.44, 95% CI: 1.30-1.60) and hip (csBMD HR = 1.76, 95% CI: 1.39-2.23) fracture; and tvBMD with increased risk of any-type (HR = 1.62, 95% CI: 1.45-1.80) and hip fracture (HR = 2.44, 95% CI: 1.88-3.15). Inclusion of aBMD in models with tvBMD or csBMD resulted in high multicollinearity and unreliable coefficient parameters (VIF > 5). The effect of csBMD was largely attenuated after inclusion of tvBMD in the same model for both any-type (csBMD HR = 0.96, 95% CI: 0.81-1.13; tvBMD HR = 1.67, 95% CI: 1.41-1.98) and hip (csBMD HR = 0.83, 95% CI: 0.58-1.21; tvBMD HR = 2.82, 95% CI: 1.94-4.10) fractures. Similar results were observed at the neck and intertrochanteric regions. DXA-derived 3D modeled parameters are highly correlated to aBMD and do not provide additional value for the estimation of fracture risk beyond aBMD alone.

It's been proposed that bone adaptation is "error-driven," meaning bone is more sensitive to non-physiological loading (eg, loading in a non-physiological direction). However, the effect of physiological vs non-physiological loading on bone adaptation and its underlying mechanism are not fully understood. We hypothesized that loading in a non-physiological direction would increase osteogenesis via enhancing fluid flow within the lacunocanalicular network (LCN), independent of the strain magnitude. To test this hypothesis, we first examined the effects of physiological and non-physiological direction loading on bone formation responses with axial and transversal in vivo loading models of the mouse tibia, respectively, under a strain-matched condition. Next, an in silico whole bone-LCN multiscale model was developed to compute loading-induced strains and fluid shear stresses (FSSs) within the LCN. Finally, regression analyses were performed to examine the spatial correlations between bone mechanoresponses and FSS (and strain). Results showed that the transversal loading led to an increased cortical bone response compared to the axial loading even though the strains were matched. The transversal loading-induced increase in bone response was associated with enhanced lacunocanalicular fluid flow rather than strain. Additionally, we found strong correlations existed between bone mechanoresponses and FSS, whereas no correlation was detected between bone responses and strain. These results support our hypothesis and may explain why bone adaptation is more sensitive to loading in a non-physiological direction. The findings also highlight the key role of the fluid dynamic microenvironment within LCN in regulating bone mechanoadaptation.

Romosozumab is a monoclonal antibody against sclerostin that initially exhibits potent anabolic effects in treating osteoporosis. However, its efficacy diminishes after 6 mo, with bone formation markers declining despite continued therapy. We hypothesized that increased levels of Dickkopf-1 (Dkk1), a Wnt pathway inhibitor, may contribute to this attenuation by suppressing osteoblast activity. We conducted a 12-mo prospective observational study on postmenopausal osteoporosis naïve to anti-osteoporosis treatment treated with romosozumab. Serum levels of Dkk1, procollagen type I N-terminal propeptide (P1NP), C-terminal telopeptide of type I collagen (CTX), and sclerostin were measured at baseline (M0) and at 3 (M3), 6 (M6), and 12 mo (M12). BMD at the LS, FN, and TH was assessed at M0, M6, and M12. Associations between Dkk1 and P1NP were analyzed using linear mixed-effects models. Dkk1 levels increased significantly from 38.9 pmol/L at M0 to 44.2 pmol/L at M12 (p = .003). P1NP increased from 89.4 ng/mL at M0 to 115.4 ng/mL at M3 (p = .004) but decreased to 61.5 ng/mL by M12 (p < .001). CTX decreased significantly throughout the study (p < .001). BMD increased significantly at all sites by M12 (LS + 13.8%, FN + 6.3%, TH + 4.7%; all p < .01). An inverse association was found between Dkk1 increase and P1NP decrease between M3 and M12 (estimate = -0.909; p = .032). Romosozumab treatment is associated with a significant rise in Dkk1 levels, which correlates with a decrease in bone formation markers over time. Dkk1 may attenuate the anabolic effects of romosozumab by inhibiting Wnt signaling.

Due to successful maternal antiretroviral therapy (ART), pediatric HIV infections have declined, leading to a growing population of children HIV-exposed uninfected (CHEU) in Sub-Saharan Africa. However, studies report poorer growth and development in CHEU versus children HIV-unexposed uninfected (CHUU), raising concerns about maternal HIV and ART exposure, particularly Tenofovir Disoproxil Fumarate (TDF). This analysis of data from the Gumba study compares growth trajectories, bone mineral accretion, and biochemical markers of growth and bone metabolism to age 18 months in Ugandan CHEU, exposed to maternal HIV and TDF-containing ART in utero and via breastmilk (n=85), and CHUU peers (n=80). The groups had similar weight and length 2 weeks after birth (WK2), but, despite higher exclusive breastfeeding rates, CHEU had slower growth by WK14 and ~0.5 kg lower body weight and fat mass by WK26. Growth faltering occurred in both groups from WK26, with widening differences: by WK78, 59% of CHEU were stunted compared to 33% of CHUU. CHEU had lower whole-body bone mineral content and bone area at WK14 and WK26 (Pinteraction: 0.03 and 0.0003 respectively), but similar whole-body areal bone mineral density before and after size adjustment, indicating accrued bone mineral was appropriate for their slower growth. There were no group differences in biochemical markers of growth or bone formation. However, CHEU had higher C-terminal telopeptide (CTX), a marker of bone resorption, at WK14 (group difference (95% confidence interval): +50.9 (24.1)%, P <0.001) coinciding with higher maternal CTX concentrations, and at WK78 (+45.6 (28.9)%, P <0.05). These findings suggest early onset growth deficits and altered bone metabolism in CHEU by 3 months of age, possibly linked to the TDF-containing ART initiated during pregnancy and/or disruptions in bone metabolism observed in their mothers. Further studies are needed to investigate the mechanisms and long-term implications for growth and bone health in CHEU.

Tumor-induced osteomalacia (TIO) is an ultrarare paraneoplastic syndrome of abnormal phosphate and vitamin D metabolism secondary to the overproduction of fibroblast growth factor 23 by small-sized mesenchymal tumors typically located in soft tissues and bone. The tumor has adverse effects on bone and patients complain of skeletal symptoms and, in severe cases, they suffer multiple devastating fractures. Specific features may characterize the histology of tumors located in bone with respect to those found in extra-skeletal sites. Indeed, the matrix may contain foci resembling primitive cartilage and osteoid. Light microscopy of bone biopsy samples reveal accumulation of osteoid due to thickening of osteoid seams and, if tetracyclines were sequentially administrated, fluorescence microscopy reveals prolongation of the mineralization lag time. Areal BMD assessed by DXA is significantly lower at both the lumbar and femoral sites in patients with TIO and values of trabecular bone score are significantly reduced with respect to healthy individuals. Patients with TIO are also characterized by significant impairment in bone quality at both the trabecular and cortical compartment when evaluated by HR-pQCT. Successful surgical removal of the causative tumor completely reverts biochemical abnormalities. BMD accrual is impressive in the short term at the central (spine and hip) level but may take longer to improve, together with microstructural parameters, at peripheral sites (radius and tibia). Future studies should address effects of long-term treatment on quality-of-life outcomes related to irreversible events, such as vertebral fractures. This is particularly important in patients with a heavy burden due to a long-standing disease.

Biological age may better predict health outcomes than chronological age by capturing individual heterogeneity in aging. We investigated whether accelerated spine aging, estimated from DXA vertebral fracture assessment (VFA) using deep learning, predicts fracture and mortality independently of age, vertebral fracture (VF), and BMD. A convolutional neural network model to estimate age from lateral spine radiographs was trained in a Korean cohort (VERTE-X, n = 10 341). Among 27 601 adults aged ≥50 who underwent DXA VFA in Manitoba, Canada (2010-2023), the pre-trained model was fine-tuned to DXA VFA images using 20% randomly sampled subset. Among remaining 80% set, test set included 8810 individuals who completed DXA before 2017 as the outcomes were ascertained through 2018. Predicted spine age difference (PAD = spine age-chronological age) was calculated in the test set. During a mean follow-up of 3.9 yr, 899 incident fractures and 969 deaths occurred. Spine age positively correlated with chronological age (r = 0.89), with a mean difference of 0.0 yr (SD = 3.4). Factors associated with higher PAD include VFs (+1.02 yr), nonvertebral fracture history (+0.22), generalized spine structural artifacts (+1.45), smoking (+1.20), and lower FN BMD (+0.60 per T-score decrement), collectively explaining 66% of PAD variance. Each SD increase in PAD was associated with higher risk of any (adjusted hazard ratio = 1.11), nonvertebral (1.10), major osteoporotic (1.12), and hip fracture (1.25), and mortality (1.12), independent of covariates (all p < .05). In summary, accelerated spine aging detected from DXA VFA predicts fracture and mortality risk independently of age, clinical risk factors, VF, spine structural artifacts, and BMD in individuals at high risk of fracture, supporting its potential to enhance fracture risk assessment.

Type 2 diabetes mellitus (T2DM) is common in patients with chronic kidney disease (CKD). Both conditions associate with an increased fracture risk, with proposed etiology including impaired bone quantity and quality. This cross-sectional study examined the bone phenotype in patients with T2DM and kidney failure and explored the role of glycemic control on the bone phenotype. To do so laboratory parameters of mineral metabolism (including sclerostin) and bone turnover markers (BTM) (bone-specific alkaline phosphatase (BALP), trimeric pro-collagen type I N-terminal propeptide (intact PINP) and tartrate-resistant acid phosphatase isoform 5b (TRACP5b)) were assessed in 647 patients with kidney failure, of which 102 had T2DM (median hemoglobin A1c (HbA1c) of 6.2%), at time of kidney transplantation. Patients with type 1 DM were excluded. Bone mineral density (BMD, n = 555) by densitometry, and bone histomorphometry (n = 188) were available for subsets, and correlations between HbA1c and both BTM and BMD were examined. This study found that intact PINP was lower (68 vs. 82 μg/L, p = .03) while sclerostin was higher (2.1 vs. 1.8 ng/mL, p = .04) in T2DM versus non-T2DM in unadjusted analysis. BMD at the lumbar spine (Z-score - 0.066 vs. -0.760, p < .001) and femoral neck (Z-score - 0.680 vs. -0.965, p = .04) were higher in T2DM, and T2DM was in multivariable regression analysis identified as a significant determinant of lumbar spine BMD, independent of age, sex, and BMI. Bone histomorphometric parameters did not differ between groups. A correlation between HbA1c and BTM and BMD was present, but only in non-T2DM (BALP (ρ = -0.12, p = .007), intact PINP (ρ = 0.14, p = .002), TRACP5b (ρ = -0.13, p = .003), BMD at lumbar spine (ρ = 0.12, p = .008), femoral neck (ρ = 0.11, p = .02), and total hip (ρ = 0.17, p < .001)). In conclusion, patients with kidney failure and T2DM have preserved BMD compared to patients without diabetes. Our findings suggest a role for hyperglycemia as a determinant of the bone phenotype.