Systemic markers of microvascular disease and bone mineral density in older adults

Summary

Here we report that abnormal brain white matter and, to a lesser extent, albuminuria are associated with reduced bone mineral density in the hip, spine, and total body in men and women. These findings may explain the increased hip fracture risk reported in some studies in association with microvascular disorders.

Introduction

Markers of microvascular disease have been individually associated with increased risk of osteoporotic fractures in some studies. Here, we examine whether these markers are associated with reduced bone mineral density (BMD) individually and together.

Methods

BMD testing using dual x-ray absorptiometry of the hip, lumbar spine, and total body was performed in 1473 participants from the Cardiovascular Health Study (mean age ~ 78 years): 1215 were assessed for urinary albumin-creatinine ratio, 944 for abnormal white matter disease (AWMD) by brain MRI, and 541 for retinal vascular disease with fundus photographs. Linear regression models were used to evaluate the cross-sectional association of each marker with BMD accounting for potentially confounding factors.

Results

AWMD was associated with lower hip, spine, and total body BMD in women (β ?3.08 to ?4.53; p < 0.01 for all) and lower hip and total body BMD in men (β ?2.90 to ?4.24; p = 0.01–0.03). Albuminuria was associated with lower hip (β ?3.37; p = .05) and total body (β ?3.21; p = .02) BMD in men, but not in women. The associations of AWMD and albuminuria with BMD persisted with mutual adjustment and appeared to be additive to each other. Retinal vascular disease was not associated with BMD in men or women.

Conclusion

AWMD and, to a lesser extent, albuminuria were independently associated with lower BMD, suggesting that microvascular disease may play a role in the pathogenesis of reduced BMD. These findings need to be confirmed by longitudinal studies.

     

Associations of total and free 25OHD and 1,25(OH)<Subscript>2</Subscript>D with serum markers of inflammation in older men

Summary

Vitamin D is hypothesized to suppress inflammation. We tested total and free vitamin D metabolites and their association with inflammatory markers. Interleukin-6 levels were lower with higher 25-hydroxyvitamin D. 1,25-dihydroxyvitamin D and free 25OHD associations mirrored those of 25OHD. However, associations for the two metabolites diverged for tumor necrosis factor alpha (TNF-α) soluble receptors.

Introduction

Vitamin D is hypothesized to suppress inflammation, and circulating 25-hydroxyvitamin D (25OHD) and inflammatory markers are inversely correlated. However, total serum 25OHD may not be the best indicator of biologically active vitamin D.

Methods

We tested serum total 25OHD, total 1,25(OH)₂D, vitamin D binding protein (DBP), and estimated free 25OHD and free 1,25(OH)₂D associations with inflammatory markers serum interleukin-6 (IL-6), TNF-α and their soluble receptors, interleukin-10 (IL-10), and C-reactive protein (CRP) as continuous outcomes and the presence of ≥2 inflammatory markers in the highest quartile as a dichotomous outcome, in a random subcohort of 679 men in the Osteoporotic Fractures in Men (MrOS) study.

Results

IL-6 was lower in men with higher 25OHD (?0.23 μg/mL per standard deviation (SD) increase in 25OHD, 95 % confidence intervals (CI) ?0.07 to ?0.38 μg/mL) and with higher 1,25(OH)₂D (?0.20 μg/mL, 95 % CI ?0.0004 to ?0.39 μg/mL); free D associations were slightly stronger. 25OHD and DBP, but not 1,25(OH)₂D, were independently associated with IL-6. TNF-α soluble receptors were inversely associated with 1,25(OH)₂D but positively associated with 25OHD, and each had independent effects. The strongest association with ≥2 inflammatory markers in the highest quartile was for free 1,25(OH)₂D (odds ratios (OR) 0.70, 95 % CI 0.54 to 0.89 per SD increase in free 1,25(OH)₂D).

Conclusions

Associations of 1,25(OH)₂D and free 25OHD with IL-6 mirrored those of 25OHD, suggesting that 1,25(OH)₂D and free D do not improve upon 25OHD in population-based IL-6 studies. However, associations for the two metabolites diverged for TNF-α soluble receptor, warranting examination of both metabolites in studies of TNF-α and its antagonists.

     

Secular Trends in Hip Fractures Worldwide: Opposing Trends East Versus West

Despite wide variations in hip rates fractures worldwide, reasons for such differences are not clear. Furthermore, secular trends in the age‐specific hip fracture rates are changing the world map of this devastating disease, with the highest rise projected to occur in developing countries. The aim of our investigation is to systematically characterize secular trends in hip fractures worldwide, examine new data for various ethnic groups in the United States, evidence for divergent temporal patterns, and investigate potential contributing factors for the observed change in their epidemiology. All studies retrieved through a complex Medline Ovid search between 1966 and 2013 were examined. For each selected study, we calculated the percent annual change in age‐standardized hip fracture rates de‐novo. Although occurring at different time points, trend breaks in hip fracture incidence occurred in most Western countries and Oceania. After a steep rise in age‐adjusted rates in these regions, a decrease became evident sometimes between the mid‐seventies and nineties, depending on the country. Conversely, the data is scarce in Asia and South America, with evidence for a continuous rise in hip fracture rates, with the exception of Hong‐Kong and Taiwan that seem to follow Western trends. The etiologies of these secular patterns in both the developed and the developing countries have not been fully elucidated, but the impact of urbanization is at least one plausible explanation. Data presented here show close parallels between rising rates of urbanization and hip fractures across disparate geographic locations and cultures. Once the proportion of the urban population stabilized, hip fracture rates also stabilize or begin to decrease perhaps due to the influence of other factors such as birth cohort effects, changes in bone mineral density and BMI, osteoporosis medication use and/or lifestyle interventions such as smoking cessation, improvement in nutritional status and fall prevention. © 2014 American Society for Bone and Mineral Research.     

Inflammatory Markers and Risk of Hip Fracture in Older White Women: The Study of Osteoporotic Fractures

Hip fractures are the most devastating consequence of osteoporosis and impact 1 in 6 white women leading to a two‐ to threefold increased mortality risk in the first year. Despite evidence of inflammatory markers in the pathogenesis of osteoporosis, few studies have examined their effect on hip fracture. To determine if high levels of inflammation increase hip fracture risk and to explore mediation pathways, a case‐cohort design nested in a cohort of 4709 white women from the Study of Osteoporotic Fractures was used. A random sample of 1171 women was selected as the subcohort (mean age 80.1 ± 4.2 years) plus the first 300 women with incident hip fracture. Inflammatory markers interleukin‐6 (IL‐6) and soluble receptors (SR) for IL‐6 (IL‐6 SR) and tumor necrosis factor (TNF SR1 and TNF SR2) were measured, and participants were followed for a median (interquartile range) of 6.3 (3.7, 6.9) years. In multivariable models, the hazard ratio (HR) of hip fracture for women in the highest inflammatory marker level (quartile 4) was 1.64 (95% confidence interval [CI], 1.09–2.48, p trend = 0.03) for IL‐6 and 2.05 (95% CI, 1.35–3.12, p trend <0.01) for TNF SR1 when compared with women in the lowest level (quartile 1). Among women with 2 and 3–4 inflammatory markers in the highest quartile, the HR of hip fracture was 1.51 (95% CI, 1.07–2.14) and 1.42 (95% CI, 0.87–2.31) compared with women with zero to one marker(s) in the highest quartile (p trend = 0.03). After individually adjusting for seven potential mediators, cystatin‐C (a biomarker of renal function) and bone mineral density (BMD) attenuated HRs among women with the highest inflammatory burden by 64% and 50%, respectively, suggesting a potential mediating role. Older white women with high inflammatory burden are at increased risk of hip fracture in part due to poor renal function and low BMD. © 2014 American Society for Bone and Mineral Research.     

Effects of hormone replacement therapy on clinical fractures and height loss: The Heart and Estrogen/Progestin Replacement Study (HERS)

PURPOSE: To determine if estrogen plus progestin reduces the incidence of fractures or height loss in postmenopausal women with coronary disease. SUBJECTS AND METHODS: We enrolled 2,763 postmenopausal women with coronary disease and with an intact uterus into the Heart Estrogen/progestin Replacement Study, a randomized double-blind, placebo-controlled secondary prevention trial of cardiovascular disease. Radiographically documented clinical fractures were a prespecified secondary endpoint. Height loss was used as a surrogate for vertebral fractures. The average age of the women was 66.7 +/- 6.7 years, and fewer than 15% of the women had osteoporosis based on their bone density. Women were randomly assigned to either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily (n = 1,380) or placebo (n = 1,383). Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment were taking it at the end of 1 year, and 64% at the end of the study. RESULTS: During 10,554 person years of follow-up, 286 women experienced a fracture: 138 in the treatment group (26.3 per 1,000 person years) and 148 in the placebo group (28.0 per 1,000 person years); relative hazard, 0.94; 95% confidence interval 0.8 to 1.2, P = 0.61). These included 58 wrist fractures (1.01; 0.6 to 1.7); 27 hip fractures (1.09; 0.5 to 2.3); 32 spine fractures (0.69; 0.3 to 1.4), and 192 other fractures (0.91; 0.7 to 1.2). There was no difference in average height loss between the treatment and placebo groups or in the percent of women who lost more than 2 cm in height: 10.6% in the treatment group and 12.1% in the placebo group. CONCLUSIONS: There was no evidence of a reduction in the incidence of fractures or rate of height loss in older women not selected for osteoporosis. Randomized studies are needed to clarify the effect of hormone replacement therapy on fracture risk among women with and without osteoporosis.     

巨噬细胞迁移抑制因子通过CC趋化因子配体2诱导巨噬细胞聚集

巨噬细胞迁移抑制因子最初是由于能抑制体外巨噬细胞随机迁移而被发现,现在它作为一种重要的调节因子参与一系列炎症性疾病过程.我们最近发现,巨噬细胞迁移抑制因子的缺失使一些由炎症介质诱发的白细胞-内皮细胞相互作用减弱,提示巨噬细胞迁移抑制因子在炎症反应中起作用的机制之一是促进白细胞聚集.……     

Syngeneic transplantation with peripheral blood mononuclear cells collected after the administration of recombinant human granulocyte colony-stimulating factor

Five syngeneic transplants were performed in four patients following myeloablative therapy using unmodified peripheral blood mononuclear cells (PBMCs) collected after the administration of recombinant human granulocyte colony stimulating factor (rhG-CSF) to normal donors. The only toxicity experienced by the four normal donors was bone pain. Four patients received two collections of PBMCs, and a second transplant was performed in one patient with one collection. The patients received a median of 20.53 x 10(8) total nucleated cells/kg (range 20 to 25.5), 11.3 x 10(8) total mononuclear cells/kg (range 6.52 to 17.2), 113.1 x 10(4)/kg CFU-GM (range 46.7 to 211.8) and 9.6 x 10(6) CD34+ cells/kg (range 1.6 to 12.6) Post-transplant growth factors were not administered. The median time to an absolute neutrophil count greater than 0.5 x 10(9)/L was 14 days (range 10 to 18). The median time to platelet transfusion independence was 11 days (range 10 to 13). Two patients had the number of CD3+ T lymphocytes determined in the pheresis product. An average of 3.04 x 10(10) CD3+ cells were collected per pheresis. This represents an approximate 1 log increase over the number of T lymphocytes in a typical bone marrow transplant. Rh-GCSF can be used to mobilize peripheral blood progenitor cells from normal donors with minimal toxicity. Studies of allogeneic transplants using PBMCs collected after rhG-CSF administration to determine permanent grafting ability and the incidence and severity of graft-versus-host disease are warranted.     

Retrovirally marked CD34-enriched peripheral blood and bone marrow cells contribute to long-term engraftment after autologous transplantation

We report here on a preliminary human autologous transplantation study of retroviral gene transfer to bone marrow (BM) and peripheral blood (PB)-derived CD34-enriched cells. Eleven patients with multiple myeloma or breast cancer had cyclophosphamide and filgrastim-mobilized PB cells CD34-enriched and transduced with a retroviral marking vector containing the neomycin resistance gene, and CD34-enriched BM cells transduced with a second marking vector also containing a neomycin resistance gene. After high-dose conditioning therapy, both transduced cell populations were reinfused and patients were followed over time for the presence of the marker gene and any adverse effects related to the gene-transfer procedure. All 10 evaluable patients had the marker gene detected at the time of engraftment, and 3 of 9 patients had persistence of the marker gene for greater than 18 months posttransplantation. The marker gene was detected in multiple lineages, including granulocytes, T cells, and B cells. The source of the marking was both the transduced PB graft and the BM graft, with a suggestion of better long-term marking originating from the PB graft. The steady- state levels of marking were low, with only 1:1000 to 1:10,000 cells positive. There was no toxicity noted, and patients did not develop detectable replication-competent helper virus at any time posttransplantation. These results suggest that mobilized PB cells may be preferable to BM for gene therapy applications and that progeny of mobilized peripheral blood cells can contribute long-term to engraftment of multiple lineages.