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Hip fractures are associated with significant disability, high cost, and mortality. However, the exact biological mechanisms underlying susceptibility to hip fractures remain incompletely understood. In an exploratory search of the underlying biology as reflected through the circulating proteome, we performed a comprehensive Circulating Proteome Association Study (CPAS) meta-analysis for incident hip fractures. Analyses included 6430 subjects from two prospective cohort studies (Cardiovascular Health Study and Trøndelag Health Study) with circulating proteomics data (aptamer-based 5 K SomaScan version 4.0 assay; 4979 aptamers). Associations between circulating protein levels and incident hip fractures were estimated for each cohort using age and sex-adjusted Cox regression models. Participants experienced 643 incident hip fractures. Compared with the individual studies, inverse-variance weighted meta-analyses yielded more statistically significant associations, identifying 23 aptamers associated with incident hip fractures (conservative Bonferroni correction 0.05/4979, P  < 1.0 × 10−5). The aptamers most strongly associated with hip fracture risk corresponded to two proteins of the growth hormone/insulin growth factor system (GHR and IGFBP2), as well as GDF15 and EGFR. High levels of several inflammation-related proteins (CD14, CXCL12, MMP12, ITIH3) were also associated with increased hip fracture risk. Ingenuity pathway analysis identified reduced LXR/RXR activation and increased acute phase response signaling to be overrepresented among those proteins associated with increased hip fracture risk. These analyses identified several circulating proteins and pathways consistently associated with incident hip fractures. These findings underscore the usefulness of the meta-analytic approach for comprehensive CPAS in a similar manner as has previously been observed for large-scale human genetic studies. Future studies should investigate the underlying biology of these potential novel drug targets. [ABSTRACT FROM AUTHOR]

Osteoporotic fractures occur in almost half of patients with a spinal cord injury (SCI) and are associated with significant morbidity and excess mortality. Paralyzed Veterans Administration (PVA) guidelines suggest that adequate calcium and vitamin D intake is important for skeletal health, however, the association of these supplements with osteoporotic fracture risk is unclear. To determine the association of filled prescriptions for calcium and vitamin D with fracture risk in Veterans with an SCI. The 5897 persons with a traumatic SCI of at least 2 years' duration (96% male; 4% female) included in the VSSC SCI/D Registry in FY2014 were followed from FY2014 to FY2020 for incident upper and lower extremity fractures. Filled daily prescriptions for calcium or vitamin D supplements for ≥6 months with an adherence ≥80% were examined. Filled prescriptions for calcium (hazard ratio [HR] 0.65; 95% CI, 0.54-0.78) and vitamin D (HR 0.33; 95% CI, 0.29-0.38) supplements were associated with a significantly decreased risk for incident fractures. Calcium and vitamin D supplements are associated with decreased risk of fracture, supporting PVA guidelines that calcium and vitamin D intake are important for skeletal health in persons with an SCI. [ABSTRACT FROM AUTHOR]

Objective: Branched chain amino acids (BCAA) are building blocks for protein, an essential component of bone. However, the association of plasma levels of BCAA with fractures in populations outside of Hong Kong or with hip fractures in particular is not known. The purpose of these analyses was to determine the relationship of BCAA including valine, leucine, and isoleucine and total BCAA (SD of the sum of Zscores for each BCAA) with incident hip fractures and bone mineral density (BMD) of the hip and lumbar spine in older African American and Caucasian men and women in the Cardiovascular Health Study. Design: Longitudinal analyses of association of plasma levels of BCAA with incident hip fractures and cross-sectional BMD of the hip and lumbar spine from the Cardiovascular Health Study. Setting: Community. Participants: A total of 1850 men (38% of cohort) and women; mean age 73 years. Main Outcome Measures: Incident hip fractures and cross-sectional BMD of the total hip, femoral neck, and lumbar spine. Results: In fully adjusted models, over 12 years of follow-up, we observed no significant association between incident hip fracture and plasma values of valine, leucine, isoleucine, or total BCAA per 1 SD higher of each BCAA. Plasma values of leucine but not valine, isoleucine, or total BCAA, were positively and significantly associated with BMD of the total hip (P = .03) and femoral neck (P = .02), but not the lumbar spine (P = .07). Conclusions: Plasma levels of the BCAA leucine may be associated with higher BMD in older men and women. However, given the lack of significant association with hip fracture risk, further information is needed to determine whether BCAAs would be novel targets for osteoporosis therapies. [ABSTRACT FROM AUTHOR]

Background: The prevention of lower extremity fractures and fracture-related morbidity and mortality is a critical component of health services for adults living with chronic spinal cord injury (SCI). Methods: Established best practices and guideline recommendations are articulated in recent international consensus documents from the International Society of Clinical Densitometry, the Paralyzed Veterans of America Consortium for Spinal Cord Medicine and the Orthopedic Trauma Association. Results: This review is a synthesis of the aforementioned consensus documents, which highlight the pathophysiology of lower extremity bone mineral density (BMD) decline after acute SCI. The role and actions treating clinicians should take to screen, diagnose and initiate the appropriate treatment of established low bone mass/osteoporosis of the hip, distal femur or proximal tibia regions associated with moderate or high fracture risk or diagnose and manage a lower extremity fracture among adults with chronic SCI are articulated. Guidance regarding the prescription of dietary calcium, vitamin D supplements, rehabilitation interventions (passive standing, functional electrical stimulation (FES) or neuromuscular electrical stimulation (NMES)) to modify bone mass and/or anti-resorptive drug therapy (Alendronate, Denosumab, or Zoledronic Acid) is provided. In the event of lower extremity fracture, the need for timely orthopedic consultation for fracture diagnosis and interprofessional care following definitive fracture management to prevent health complications (venous thromboembolism, pressure injury, and autonomic dysreflexia) and rehabilitation interventions to return the individual to his/her pre-fracture functional abilities is emphasized. Conclusions: Interprofessional care teams should use recent consensus publications to drive sustained practice change to mitigate fracture incidence and fracture-related morbidity and mortality among adults with chronic SCI. [ABSTRACT FROM AUTHOR]

Introduction: Patients with systemic lupus erythematosus (SLE) are at elevated risk for Q10 cardiovascular disease (CVD) due to accelerated atherosclerosis. Compared to heathy control subjects, lupus patients have higher volumes and densities of thoracic aortic perivascular adipose tissue (PVAT), which independently associates with vascular calcification, a marker of subclinical atherosclerosis. However, the biological and functional role of PVAT in SLE has not been directly investigated. Methods: Using mouse models of lupus, we studied the phenotype and function of PVAT, and the mechanisms linking PVAT and vascular dysfunction in lupus disease. Results and discussion: Lupus mice were hypermetabolic and exhibited partial lipodystrophy, with sparing of thoracic aortic PVAT. Using wire myography, we found that mice with active lupus exhibited impaired endothelium-dependent relaxation of thoracic aorta, which was further exacerbated in the presence of thoracic aortic PVAT. Interestingly, PVAT from lupus mice exhibited phenotypic switching, as evidenced by "whitening" and hypertrophy of perivascular adipocytes along with immune cell infiltration, in association with adventitial hyperplasia. In addition, expression of UCP1, a brown/beige adipose marker, was dramatically decreased, while CD45-positive leukocyte infiltration was increased, in PVAT from lupus mice. Furthermore, PVAT from lupus mice exhibited a marked decrease in adipogenic gene expression, concomitant with increased pro-inflammatory adipocytokine and leukocyte marker expression. Taken together, these results suggest that dysfunctional, inflamed PVAT may contribute to vascular disease in lupus. [ABSTRACT FROM AUTHOR]

Background: Previous studies have suggested an association between bone mineral density (BMD) and heart failure (HF) risk that may be racedependent. Methods: We evaluated the relationship between BMD and incident HF in a cohort of older adults, the Health, Aging, and Body Composition (Health ABC) study (n = 2835), and next performed a pooled analysis involving a second older cohort, the Cardiovascular Health Study (n = 1268). Hip BMD was measured by dual-energy X-ray absorptiometry in both cohorts and spine BMD by computed tomography in a subset from Health ABC. Results: In Health ABC, lower BMD at the total hip was associated with higher incident HF in Black women after multivariable adjustment. Similar associations were found for BMD at the femoral neck and spine. In both cohorts, pooled analysis again revealed an association between lower total hip BMD and increased risk of HF in Black women (HR = 1.41 per 0.1-g/cm² decrement [95% CI = 1.23–1.62]), and showed the same to be true for White men (HR = 1.12 [1.03–1.21]). There was a decreased risk of HF in Black men (HR 0.80 [0.70–0.91]), but no relationship in White women. The associations were numerically stronger with HFpEF for Black women and White men, and with HFrEF for Black men. Findings were similar for femoral neck BMD. Sensitivity analyses delaying HF follow-up by 2 years eliminated the association in Black men. Conclusions: Lower BMD was associated with higher risk of HF and especially HFpEF in older Black women and White men, highlighting the need for additional investigation into underlying mechanisms. [ABSTRACT FROM AUTHOR]