Journal of Bone and Mineral Research最新文献

Bone turnover assessment and monitoring are essential for chronic kidney disease (CKD)-associated bone care. Patients with CKD suffer from significantly elevated fracture risk due to abnormally high or low bone turnover, which requires diametrically opposite treatments informed by patient-specific bone turnover data. However, a reliable, accessible, non-invasive bone turnover assessment and monitoring tool remains an unmet clinical need. Combining time-lapse (TL) analysis with high-resolution peripheral quantitative computed tomography (HR-pQCT) scans obtained over time allows for in vivo temporospatial bone remodeling assessment. This study aimed to evaluate the feasibility of applying TL HR-pQCT to assess and monitor local bone formation and resorption in patients with CKD. A customized TL HR-pQCT pipeline was developed on a second-generation HR-pQCT platform and optimized using ex vivo cadaveric phantom and in vivo scan-rescan HR-pQCT images. The annualized least significant change in bone formation and resorption were evaluated using in vivo longitudinal reproducibility images. Finally, the feasibility of the TL HR-pQCT pipeline in assessing and monitoring bone turnover was evaluated in patients with end stage kidney disease (ESKD; n = 9). We found that a 2-month time-lapse period was sufficient for the TL HR-pQCT pipeline to reliably assess and monitor local bone turnover in a cohort of patients with ESKD. We also demonstrated the importance of characterizing TL HR-pQCT precision metrics using longitudinal baseline/follow-up rather than short-term scan-rescan datasets. The TL HR-pQCT pipeline assessed a range of bone formation metrics consistent with the gold standard histomorphometric bone formation reported in the literature for patients with CKD and ESKD. Our findings highlight that TL HR-pQCT holds promise as a "virtual bone biopsy" that reliably assesses and monitors local bone turnover for CKD bone care. Subsequent work will focus on validating this TL HR-pQCT pipeline against the gold standard bone biopsy with quantitative histomorphometry.

Bone mineral density (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 (i.e., 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 < 0.00068). 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 < 0.00068). 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.

Calcium supplementation before exercise attenuates the decrease in serum calcium and increase in PTH and bone resorption. This study investigated the effect of calcium supplementation on calcium and bone metabolism during load carriage in women. Forty-eight women completed two load carriage sessions (load carriage 1 n = 48; load carriage 2 n = 40) (12.8 km in 120 min carrying 20 kg) 60 min after consuming either 1000 mg calcium (Calcium) or nothing (Control) in a randomised order. Pre- and post-exercise urine samples were analysed for calcium isotope ratio (δ44/42Ca). Fasted blood samples were taken before (pre-exercise), during (0, 20, 40, 60, 80, 100, 120 min), and after (+15, +30, +60, +90 min) exercise and analysed for markers of calcium and bone metabolism. There was no effect of load carriage or supplementation on urine δ44/42Ca (P≥.110). Serum δ44/42Ca did not change with load carriage in Control (P=.617) but increased in Calcium (P=.003) and was higher at 120 min in Calcium vs Control (P=.018). Ionised calcium (iCa) decreased from pre-exercise to all exercise time-points (P<.001); iCa was higher in Calcium than Control throughout (P<.001). PTH increased from pre-exercise to 120 min in Control (P<.001) but decreased from pre-exercise to all time-points in Calcium (P<.001). PTH was higher in Control than Calcium from 0 to +90 min (P<.001). βCTX decreased from pre-exercise to 20 to +15 min in Control (P≤.004); βCTX decreased from pre-exercise to 0 to +90 min in Calcium (P<.001). βCTX was lower in Calcium than Control from 20 to +90 min (P≤.036). A 1000 mg calcium supplement before load carriage promotes bone calcium balance and prevents disruptions to bone and calcium homeostasis.

We previously documented successful resolution of skeletal and dental disease in the infantile and late-onset murine models of hypophosphatasia (HPP), with a single injection of an adeno-associated serotype 8 vector encoding mineral-targeted TNAP (AAV8-TNAP-D10). Here, we conducted dosing studies in both HPP mouse models. A single escalating dose from 4x108 up to 4x1010 (vg/b) was intramuscularly injected into 4-day-old Alpl-/- mice (an infantile HPP model) and a single dose from 4x106 up to 4x109 (vg/b) was administered to 8-week-old AlplPrx1/Prx1 mice (a late-onset HPP model). Wild-type littermates were used as controls. Serum alkaline phosphatase activity was increased, and PPi levels were decreased in a dose-dependent manner in both the Alpl-/- and AlplPrx1/Prx1 models. Radiographic and μCT analysis of long bones of female and male Alpl-/- mice showed full correction of skeletal phenotype at 4x1010 vg/b. We observed full correction of the bone phenotype at 4x108 and 4x109 in female AlplPrx1/Prx1 mice, but bones remained hypomineralized with the 4x106 and 4x107 (vg/b) doses after 70 days of treatment. We observed skeletal improvements using the 4x109 (vg/b) dose, but the phenotype was not fully corrected in male AlplPrx1/Prx1. Immunohistochemistry using anti-TNAP and anti-D10 antibodies showed high immunolocalization in the femurs of female AlplPrx1/Prx1 mice, while D10 immunolocalization was high in the liver of male AlplPrx1/Prx1 mice at a dose of 4x109 (vg/b). This sex-dependent difference was not seen in the infantile HPP model. A serum proteome analysis showed enhanced inflammatory pathways in treated AlplPrx1/Prx1 males compared to treated female mice. We also found a few areas of ectopic calcification in soft organs at the highest tested dose of 4x1010 (vg/b) in Alpl-/- or 4x109 (vg/b) in the AlplPrx1/Prx1 model. This pre-clinical study will inform the design of clinical trials to develop gene therapy in early-onset and late-onset HPP patients.

Early increases in bone turnover markers (BTMs) in response to anabolic therapy correlate with 18-month bone mineral density (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 carboxy-terminal cross-linking telopeptide of type I collagen (CTX) at 1, 3, 6, and 12 months and percent increase from baseline in BMD at 12 months 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-month 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 month (r = 0.485), 3 months (r = 0.614), 6 months (r = 0.632), and 12 months (r = 0.521) were highly correlated (P<.0001) with 12-month lumbar spine BMD increases. The mean UI for abaloparatide-treated men was greater than placebo as early as 1 month (2.26 versus -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-month UI and lumbar spine BMD at 12 months 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-month lumbar spine 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. Trial registration: clinicaltrials.gov Identifier NCT03512262.

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 Bone Mineral Density Registry. The cohort included 10 250 individuals (mean 75.5 years, 94% women without CVD) with VFA (February 2010 to March 2017) were included. ML-AAC24 scores were categorized (low <2; moderate 2- < 6; high ≥6). Over follow-up (mean 3.9 years), 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 years, 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.

Achieving bone union remains a significant clinical dilemma. The use of osteoinductive agents, specifically bone morphogenetic proteins (BMPs), has gained wide attention. However, multiple side effects, including increased incidence of cancer, have renewed interest in investigating alternatives that provide safer, yet effective bone regeneration. Here we demonstrate the robust bone healing capabilities of the main megakaryocyte (MK) growth factor, thrombopoietin (TPO), and second-generation TPO agents using multiple animal models, including mice, rats, and pigs. This bone healing activity is shown in two fracture models (critical-sized defect [CSD] and closed fracture) and with local or systemic administration. Our transcriptomic analyses, cellular studies, and protein arrays demonstrate that TPO enhances multiple cellular processes important to fracture healing, particularly angiogenesis, which is required for bone union. Finally, the therapeutic potential of thrombopoietic agents is high since they are used in the clinic for other indications (eg, thrombocytopenia) with established safety profiles and act upon a narrowly defined population of cells.

Type 1 diabetes (T1D) is associated with an increased risk of hip fracture beyond what can be explained by reduced bone mineral density, possibly due to changes in bone material from accumulation of advanced glycation end-products (AGEs) and altered matrix composition, though data from human cortical bone in T1D are limited. The objective of this study was to evaluate cortical bone material behavior in T1D by examining specimens from cadaveric femora from older adults with long-duration T1D (≥50 yr; n = 20) and age- and sex-matched nondiabetic controls (n = 14). Cortical bone was assessed by mechanical testing (4-point bending, cyclic reference point indentation, impact microindentation), AGE quantification [total fluorescent AGEs, pentosidine, carboxymethyl lysine (CML)], and matrix composition via Raman spectroscopy. Cortical bone from older adults with T1D had diminished postyield toughness to fracture (-30%, p = .036), elevated levels of AGEs (pentosidine, +17%, p = .039), lower mineral crystallinity (-1.4%, p = .010), greater proline hydroxylation (+1.9%, p = .009), and reduced glycosaminoglycan (GAG) content (-1.3%, p < .03) compared to nondiabetics. In multiple regression models to predict cortical bone toughness, cortical tissue mineral density, CML, and Raman spectroscopic measures of enzymatic collagen crosslinks and GAG content remained highly significant predictors of toughness, while diabetic status was no longer significant (adjusted R2 > 0.60, p < .001). Thus, the impairment of cortical bone to absorb energy following long-duration T1D is well explained by AGE accumulation and modifications to the bone matrix. These results provide novel insight into the pathogenesis of skeletal fragility in individuals with T1D.