Journal of Bone and Mineral Research最新文献

Opportunistic screening is essential to improve the identification of individuals with osteoporosis. Our group has utilized image texture features to assess bone quality using clinical MRIs. We have previously demonstrated that greater heterogeneity of MRI texture related to history of fragility fractures, lower bone density, and worse microarchitecture. The present study investigated relationships between MRI-based texture features and biomechanical properties of bone using CT-based finite element analyses (FEA). We hypothesized that individuals with greater texture heterogeneity would have lower stiffness and failure load. Thirty individuals included in this prospective study had CT and MRI of L1 and L2 vertebrae. Using T1-weighted MR images, a gray-level co-occurrence matrix was generated to characterize the distribution and spatial organization of voxelar signal intensities to derive the following texture features: contrast (variability), entropy (disorder), angular second moment (ASM; uniformity), and inverse difference moment (IDM; homogeneity). Features were calculated in five directions relative to the image plane. Whole-bone stiffness and failure load were calculated from phantom-calibrated lumbar QCT. Mean age of subjects was 59 ± 11 years (57% female). Individuals with lower vertebral stiffness had greater texture heterogeneity; specifically, higher contrast (r = -0.54, P<.01), higher entropy (r = -0.52, P<.01), lower IDM (r = 0.54, P<.01) and lower ASM (r = 0.51, P<.01). Lower vertebral failure load and lower vBMD were similarly associated with greater texture heterogeneity. Relationships were unchanged when using the average of texture in all directions or the vertical direction in isolation. In summary, individuals with more heterogeneous MRI-based trabecular texture had lower stiffness and failure load by FEA, and lower vBMD by central quantitative CT. These results-the first relating MRI-based texture features and biomechanical properties of bone-provide further support that MRI-based texture measurements can be used to opportunistically detect skeletal fragility.

Chondrodysplasias with multiple dislocations are rare skeletal disorders characterized by hyperlaxity, joint dislocations, and growth retardation. Chondrodysplasias with multiple dislocations have been linked to pathogenic variants in genes encoding proteins involved in the proteoglycan biosynthesis. In this study, by exome sequencing analysis, we identified a homozygous nonsense variant (NM_001297654.2: c.1825C > T, p.Arg609*) in the discoidin domain receptor 1 (DDR1) gene in a patient presenting joint dislocations, hyperlaxity, and cerebellar hypoplasia. Functional studies revealed decreased proteoglycan production in patient fibroblasts. We further demonstrated that DDR1 inhibition impaired the Indian Hedgehog (IHH) signaling pathway in chondrocytes, decreased differentiation and mineralization in osteoblasts, and disrupted p38 MAPK signaling in both cell types. Additionally, we showed that DDR1 inhibition affected the non-canonical WNT signaling pathway in human skeletal cells and decreased proteoglycan production in chondrocytes. These findings suggest that DDR1 is a new gene involved in the group of chondrodysplasias with multiple dislocations and highlights its essential role in human skeletal and brain development.

Bone vasculature is richly innervated by an extensive network of sympathetic nerves. However, our understanding of bone blood flow regulation and its contribution to human bone health is limited. Here, we further our previous findings by characterizing bone vascular responses in the absence of sympathetic control - studying individuals with spinal cord injury (SCI), a population with known peripheral sympathetic disruption. We assessed tibial vascular responses to isometric handgrip exercise (IHE) in individuals with SCI (n = 12) and controls (n = 12). When sustained to fatigue, IHE increases perfusion pressure and sympathetic vasoconstriction in the non-active tissues of the legs. During IHE, we measured blood pressure, whole leg blood velocity via ultrasound, and tibial perfusion (as hemoglobin content) via near-infrared spectroscopy. Controls demonstrated active sympathetic vasoconstriction in the whole leg (i.e., increased vascular resistance, arterial pressure/leg blood velocity) and tibia (i.e., decreased hemoglobin). In contrast, SCI individuals demonstrated modest whole leg vasoconstriction with lesser increases in vascular resistance than controls (P<.04). Tibial vasculature evidenced absent or blunted vasoconstriction compared to controls (P<.01), indicated by increasing tibial hemoglobin until plateauing at higher pressure levels. This suggests that, in the absence of sympathetic control, tibial vascular response may involve other regulatory mechanisms like myogenic vasoconstriction. Lastly, we leveraged existent whole-body Dual Energy X-ray Absorptiometry scans in a subgroup of nine individuals with SCI and we found a strong relationship between leg bone mineral density (BMD) and tibial hemoglobin at end of IHE (r2 = 0.67, P<.01). Our findings indicate that in the absence of sympathetic mechanisms, myogenic control may play a compensatory role in regulating blood flow, though to a lesser extent in bone compared to muscle. The close relationship between lesser declines in bone blood content and higher BMD underscores the link between blood flow and bone health.

Duan X, et al, report that CYP4A22 loss-of-function causes a new form of vitamin D-dependent rickets. Here we describe the basis for our rejection of their proposal and provide evidence that the CYP4A22 variant that they have identified (c.901del, p.Glu301Argfs*80 (NM_001010969.4)), is a common allelic variant that is particularly prevalent in the East Asian population that includes the patients that they studied. Finally, we submit that the two patients are more likely to have X-linked Hypophosphatemic rickets than vitamin D dependent rickets.

We have proposed to the Food and Drug Administration (FDA) that treatment-related increases in total hip bone mineral density (TH BMD) at two years could be a surrogate endpoint for fracture risk reduction in clinical trials. The qualification of a surrogate includes a strong association of the surrogate with the clinical outcome. We compiled a large database of individual patient data (IPD) through the FNIH-ASBMR-SABRE project, and this analysis aimed to assess the relationship between baseline BMD and fracture risk in the placebo groups. We estimated the association of baseline TH, femoral neck (FN) and lumbar spine (LS) BMD with fracture risk using IPD from the combined placebo groups which included data from 46 666 placebo participants in 25 randomised controlled trials (RCTs). We estimated the relative risk (RR) of fracture per standard deviation (SD) decrease in baseline BMD using logistic regression models for radiographic vertebral fractures and proportional hazards models for hip, non-vertebral, "all" and "all clinical" fractures. Total person-years in the combined placebo groups was 250 662 (mean baseline age 70.2 ± 7.2 years, mean TH BMD T-score -1.97 ± 0.90). We observed significant relationships between baseline TH BMD and vertebral (RR = 1.55/SD), hip (RR = 2.27), non-vertebral (RR = 1.31), all (RR = 1.43) and all clinical (RR = 1.35) fracture risk. Fracture risk estimates were similar for FN BMD and after adjustment for age, race and study. Fracture incidence increased with decreasing TH BMD quintile, confirming the strong graded association between TH BMD and fracture risk. There was a strong relationship between LS BMD and vertebral fracture risk (RR = 1.56/SD), but only a weak association with non-vertebral (RR = 1.07) and no association with hip (RR = 1.01) fracture risk. These data support the very strong relationship between hip BMD and fracture risk and provide supporting rationale for change in TH BMD as a surrogate for fracture risk reduction in future RCTs.

Bone is a mechanosensitive organ, and its regeneration also depends on the ability of bone cells to perceive and react to mechanical stimuli. Macrophages are indispensable for bone formation, regeneration, and maintenance. Depletion of macrophages resulted in poor bone development, due to impaired vessels formation and osteogenesis. However, how mechanical stimulation stimulates macrophages during bone regeneration is unclear. As in many cell types, Piezo1 is part of the mechanotransduction in macrophages, and modulates macrophage activity. Here, we utilized conditional knockout of Piezo1 in LysM+ myeloid cells and in vivo mechanical loading to investigate the mechanoregulation of macrophages and their contribution to bone repair. We found that mechanical loading increased the ratio of CD206+ macrophages, angiogenesis-osteogenesis coupling, and cell proliferation within defect region, leading to enhanced bone regeneration. However, all the loading-induced upregulation were blunted by conditional knockout of Piezo1 in macrophages. Furthermore, we implanted wildtype bone marrow-derived macrophages into defect area in Piezo1 knockout mice. Wildtype macrophages rescued mechanosensitive angiogenesis-osteogenesis coupling and promoted bone regeneration in Piezo1 knockout mice. Together, our data showed that Piezo1 in macrophages is indispensable for loading-induced bone regeneration by stimulating macrophage polarization into the CD206+ phenotype, thereby facilitating the angiogenesis-osteogenesis coupling, promoting cell proliferation, and finally resulting in enhanced bone regeneration.

Patella fractures are not typically considered osteoporotic fractures. We compared bone mineral density (BMD) and microstructure in elderly women from a multiethnic population-based study in New York City with any history of a patella fracture (n = 27) to those without historical fracture (n = 384) and those with an adult fragility forearm fracture (n = 28) using dual energy x-ray absorptiometry (DXA) and high resolution peripheral quantitative computed tomography (HR-pQCT). Compared to those without fracture, women with patella fracture had 6.5% lower areal BMD (aBMD) by DXA only at the total hip (p=.007), while women with forearm fracture had lower aBMD at multiple sites and lower trabecular bone score (TBS), adjusted for age, body mass index, race and ethnicity (all p<.05). By HR-pQCT, adjusted radial total and trabecular (Tb) volumetric BMD (vBMD) and Tb number were 10%-24% lower while Tb spacing was 12-23% higher (all p<.05) in the fracture groups versus women without fracture. Women with a forearm, but not a patella, fracture also had lower adjusted radial cortical (Ct) area and vBMD and 21.8% (p<.0001) lower stiffness vs. women without fracture. At the tibia, the fracture groups had 9.3%-15.7% lower total and Tb vBMD (all p<.05) compared to the non-fracture group. Women with a forearm fracture also had 10.9, and 14.7% lower tibial Ct area and thickness versus those without fracture. Compared to women without fracture, tibial stiffness was 9.9% and 12% lower in the patella and forearm fracture groups, respectively (all p<.05). By HR-pQCT, the patella vs. forearm fracture group had 36% higher radial Tb heterogeneity (p<.05). In summary, women with patella fracture had Tb deterioration by HR-pQCT associated with lower tibial mechanical competence that was similar to those with fragility forearm fracture, a more universally accepted "osteoporotic" fracture. These data suggest patella fractures are associated with skeletal fragility and warrant skeletal evaluation.

Vertebral compression fractures (VFs) and spinal degeneration are both common causes of back pain, particularly in older adults. Previous cross-sectional studies have shown a potential association between these entities, but there is limited evidence on the role of VFs in spinal degeneration. In this longitudinal study, we evaluated the association between prevalent VFs and the subsequent progression of facet joint osteoarthritis (FJOA) and intervertebral disc height narrowing (DHN), using data from the Framingham Heart Study Offspring and Third Generation Multi-Detector Computed Tomography study. Summary indices representing the total burden of each spinal parameter (VFs, DHN, and FJOA) were calculated for each individual. We hypothesized that prevalent VFs are associated with worsening spinal degeneration. Three hundred and seventy (31%) of 1197 participants had a baseline (prevalent) VF. The change in summary index of DHN over the follow-up period was significantly higher in those with vs without prevalent VF (difference in change in DHN 0.38, 95% CI 0.18 to 0.59, p<.001), but the change in summary index of FJOA was similar between those with and without prevalent VF. However, once adjusted for age, sex, cohort, smoking status, BMI, and baseline DHN, the change in summary index of DHN did not differ by prevalent VF status. There was a modestly higher change in the FJOA summary index in those with prevalent VFs compared to those without in the fully adjusted model (difference in change in FJOA 0.62, 95% CI -0.01 to 1.24, p = .054), driven primarily by those with severe (grade 3) VF (difference in change in FJOA 4.48, 95% CI 1.99-6.97). Moreover, there was greater change in the summary index of FJOA with increasing severity of prevalent VF (linear trend p = .005). Beyond the established morbidity and mortality associated with VFs, our study suggests that VFs may also lead to worsening spine osteoarthritis.

Improved survival in people with cystic fibrosis (pwCF) presents new complexities of care, including CF-related bone disease, a common complication in older pwCF. The trajectory of bone loss with age in this population remains unclear. The objective of this study was to estimate the average rate of change in BMD in adults with CF. This retrospective study included adults with CF, aged 25-48 yr, followed between January 2000 and December 2021. Subjects with at least one DXA scan were included. Scans obtained posttransplantation, after the initiation of bisphosphonates or cystic fibrosis transmembrane conductance regulator modulator therapy was excluded. The primary outcome was BMD (g/cm2) at the LS and FN. A linear mixed-effects model with both random intercept and random slope terms was used to estimate the average annual change in BMD. A total of 1502 DXA scans in 500 adults (average age 28.4 y) were included. There was a statistically significant annual decline in BMD of -0.008 gm/cm2/yr (95% CI, -0.009 to -0.007) at the FN and -0.006 gm/cm2/yr (95% CI, -0.007 to -0.004) at the LS. Relative to BMD at age 25, there was a 18.8% decline at the FN by age 48 yr and a 11% decline at the LS. Pancreatic insufficient subjects had a faster rate of decline in BMD compared with pancreatic sufficient subjects. After adjusting for markers of disease severity, the annual rate of decline remained significant. Individuals with CF experience bone loss at an age when it is not anticipated, thereby entering early adulthood, where further bone loss is inevitable especially with the decrease in estrogen during menopause, with suboptimal BMD. As the CF population ages, it will become very important to consider interventions to maximize bone health.