Journal of Bone and Mineral Research最新文献

Distal radius fractures are among the most common fracture sites, with a high incidence across all age groups. High-resolution peripheral quantitative computed tomography (HR-pQCT) has enabled assessment of bone microarchitecture in vivo at the distal radius, providing new insights into the healing process. However, we have observed structural bone loss that is not captured by standard analysis. This study uses void space analysis to quantify development of localized structural bone loss during fracture healing. Twenty-six participants (21 female, 5 male, aged 18-79 years) with conservatively-treated distal radius fractures were scanned using HR-pQCT at 6 study visits post-fracture (weeks 1, 3, 5, 12, 26, and 52). Total BMD (Tt.BMD), bone volume fraction (BV/TV), and void space volume fraction (VS/TV) were measured. Grip strength relative to the non-fractured wrist and Patient Rated Wrist Evaluation (PRWE) were measured at all study visits after cast removal. The cumulative expansion of VS/TV across sequential study visits was quantified to differentiate voids that developed during healing from pre-existing void space. A five-fold increase in median VS/TV was observed during the follow-up period, from 1.0% (0.6-9.0%) to 5.5% (2.5-12.4%). Tt.BMD and BV/TV did not significantly change in this same time interval. Relative grip strength after cast removal was significantly inversely correlated with final VS/TV (⍴ = -0.63, p=.02) and cumulative expansion of new void space during healing (R = -0.67, p<.01), whereas no significant associations were found with age or PRWE. This study suggests that there are adverse changes in bone microarchitecture during fracture healing, despite the preservation of overall Tt.BMD and BV/TV in the same region. Reduced grip strength is correlated with more severe void space formation, but the mechanistic relationship requires further exploration. The formation of void spaces may have long-term implications on bone strength and could provide insight into risk of re-fracture.

Background: A significant number of kidney transplant recipients have low BMD. We hypothesized that calcitriol administration over the first year post-transplantation would protect the cortical skeleton in recipients managed without corticosteroids by suppressing PTH and bone remodeling.

Methods: In this double-blind, placebo-controlled trial, 67 participants aged ≥18 years on corticosteroid-sparing immunosuppressive regimen were randomized to daily calcitriol 0.5 mcg or placebo for 12 months after transplantation. The primary endpoint was the percent change in cortical density at the radius and tibia from pre- to post-calcitriol treatment compared to placebo as measured by HR-pQCT. Areal BMD was measured by DXA. Cortical and trabecular volumetric BMD and microarchitecture and total estimated bone strength were measured by HR-pQCT. Blood samples for bone metabolic markers were obtained at baseline, one- and twelve-months. All primary analyses were intent to treat. Safety was assessed for hypercalcemia and progression of vascular calcifications.

Results: Thirty-two participants received calcitriol and 29 received placebo; 27 and 27 participants completed the study, respectively. Most participants were male and Caucasian. Baseline Z-scores at all sites were within 0.5 SD of the general population. At 12-months post-transplantation, there were no between group differences in: areal BMD, volumetric BMD, microarchitecture or bone strength, or serum levels of bone markers. Participants with versus without bone loss had a blunted anabolic response over 12 months measured by serum bone markers. Hypercalcemia was higher in the calcitriol group compared to placebo (p<.001). No changes in arterial calcification scores were observed.

Conclusions: In this randomized placebo-controlled study of calcitriol administration in kidney transplant recipients on corticosteroid-sparing immunosuppression, calcitriol did not improve bone quality and strength but was associated with higher rates of hypercalcemia.

Vertebral fracture assessment (VFA) images from bone density machines enable the automated machine learning assessment of abdominal aortic calcification (ML-AAC), a marker of cardiovascular disease (CVD) risk. The objective of this study was to describe the risk of a major adverse cardiovascular event (MACE, from linked health records) in patients attending routine bone mineral density (BMD) testing and meeting specific criteria based on age, BMD, height loss, or glucocorticoid use have a VFA in the Manitoba BMD Registry. The cohort included 10 250 individuals (mean age 75.5 yr, 94% women without CVD) with VFA (February 2010 to March 2017). ML-AAC24 scores were categorized (low <2; moderate 2-<6; high ≥6). Over follow-up (mean 3.9 yr), 1265 people (12.3%) experienced a MACE. Among those with low, moderate, and high ML-AAC24, MACE rates per 1000 person-years were 18.4 (95% CI 16.4-20.5), 34.1 (95% CI 30.9-37.4), and 55.6 (95% CI 50.8-60.1), respectively. A similar gradient was observed after stratifying by age and sex. Incidence rate ratios (IRRs) for low vs moderate and high groups were 1.9 (95% CI 1.6-2.2) and 3.0 (95% CI 2.6-3.5), respectively. In those most likely to benefit from pharmaceutical intervention (<80 yr, not on statins), MACE rates among those with low, moderate, and high ML-AAC24 were 13.5 (95% CI 11.5-15.8), 26.0 (95% CI 22.1-30.3) and 44.1 (95% CI 37.0-52.0). Corresponding IRRs for low vs moderate 1.9 (95% CI 1.5-2.4) and high ML-AAC24 was 3.3 (95% CI 2.6-4.1]), respectively. In routine osteoporosis screening, individuals with moderate and high ML-AAC24 had substantially greater MACE rates compared to those with low ML-AAC24. Consequently, AAC detection during osteoporosis screening (especially in women) may guide intensification of preventative cardiovascular strategies.

We have proposed to the Food and Drug Administration (FDA) that treatment-related increases in total hip BMD (TH BMD) at 2 yr 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 Foundation for the National Institutes of Health-American Society for Bone and Mineral Research- A Study to Advance BMD as a Regulatory Endpoint (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 RCTs. We estimated the relative risk (RR) of fracture per 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 yr, 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.

Early increases in bone turnover markers (BTMs) in response to anabolic therapy correlate with 18-mo BMD increases in postmenopausal women with osteoporosis; however, this relationship has not been assessed in men. In this analysis, the correlation between changes from baseline in fasting intact serum procollagen type I N propeptide (PINP) and serum CTX at 1, 3, 6, and 12 mo and percent increase from baseline in BMD at 12 mo in men from the randomized phase 3 ATOM study (NCT03512262) were evaluated using Pearson's correlation coefficients. The uncoupling index (UI), a measure of the balance between markers of bone formation (PINP) and bone resorption (CTX), with positive UI favoring bone formation, was calculated. Results in men were compared to 12-mo results for women from the ACTIVE study using the z score test after Fisher's Z transformation. In abaloparatide-treated men, PINP increases at 1 mo (r = 0.485), 3 mo (r = 0.614), 6 mo (r = 0.632), and 12 mo (r = 0.521) were highly correlated (p < .0001) with 12-mo LS BMD increases. The mean UI for abaloparatide-treated men was greater than placebo as early as 1 mo (2.26 vs -0.25). At month 3, the mean UI for men was greater (1.32) than for women (0.88) (p < .001). There was a significant correlation between 3-mo UI and LS BMD at 12 mo in both men (r = 0.453; p < .001) and women (r = 0.252; p < .01). UI at months 6 and 12 were also significantly correlated with 12-mo LS BMD in men and women, but the correlation was stronger in men than women. These data support that early changes in BTMs in men treated with abaloparatide are associated with subsequent changes in BMD similar to what has been reported in women.

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 (PG) 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 PG production in patient fibroblasts. We further demonstrated that DDR1 inhibition impaired the Indian Hedgehog 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 noncanonical WNT signaling pathway in human skeletal cells and decreased PG 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.

BMD, an important marker of bone health, is regulated by a complex interaction of proteins. Plasma proteomic analyses can contribute to identification of proteins associated with changes in BMD. This may be especially informative in stages of bone accrual and peak BMD achievement (ie, adolescence and young adulthood), but existing research has focused on older adults. This analysis in the Study of Latino Adolescents at Risk for Type 2 Diabetes (SOLAR; n = 304; baseline age 8-13, 100% Hispanic) explored associations between baseline proteins (n = 653 proteins) measured with Olink plasma protein profiling and repeated annual DXA measures of BMD (average of 3.2 visits per participant). Covariate-adjusted linear mixed effect regression models were applied to estimate longitudinal protein-BMD associations using an adjusted p value cutoff (p < .00068). Identified proteins were imported into the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database to determine significantly enriched protein pathways. Forty-four proteins, many of which are involved in inflammatory processes, were associated with longitudinal changes in total body BMD, including several proteins previously linked to bone health such as osteopontin (SPP1) and microfibrillar-associated protein 5 (MFAP5; both p < .00068). These 44 proteins were associated with enrichment of pathways including PI3K-Akt signaling pathway and cytokine-cytokine receptor interaction, supporting results from existing proteomics analyses in older adults. To evaluate whether protein associations were consistent into young adulthood, linear mixed effect models were repeated in a young adult cohort (n = 169; baseline age 17-22; 62.1% Hispanic) with 346 available overlapping Olink protein measures. While there were no significant overlapping longitudinal protein associations between the cohorts, these findings suggest differences in protein regulation at different ages and provide novel insight on longitudinal protein associations with BMD in overweight/obese adolescents and young adults of primarily Hispanic origin, which may inform the development of biomarkers for bone health in youth.

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 nonactive tissues of the legs. During IHE, we measured blood pressure, whole leg blood velocity (LBV) via ultrasound, and tibial perfusion (as hemoglobin content) via near-infrared spectroscopy. Controls demonstrated active sympathetic vasoconstriction in the whole leg (ie, increased vascular resistance [VR], arterial pressure/LBV) and tibia (ie, decreased hemoglobin). In contrast, SCI individuals demonstrated modest whole leg vasoconstriction with lesser increases in VR 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 DXA scans in a subgroup of 9 individuals with SCI, and we found a strong relationship between leg BMD and tibial hemoglobin at the 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.