Fracture risk in men with prostate cancer: A population‐based study

Fractures are increased among men with prostate cancer, especially those on androgen‐deprivation therapy (ADT), but few data are available on men with localized prostate cancer. The purpose of this investigation was to estimate fracture risk among unselected community men with prostate cancer and systematically assess associations with ADT and other risk factors for fracture. In a population‐based retrospective cohort study, 742 Olmsted County, MN, men with prostate cancer first diagnosed in 1990–1999 (mean age 68.2 ± 8.9 years) were followed for 6821 person‐years. We estimated cumulative fracture incidence, assessed relative risk by standardized incidence ratios, and evaluated risk factors in time‐to‐fracture regression models. All together, 482 fractures were observed in 258 men (71 per 1000 person‐years). Overall fracture risk was elevated 1.9‐fold, with an absolute increase in risk of 9%. Relative to rates among community men generally, fracture risk was increased even among men not on ADT but was elevated a further 1.7‐fold among ADT‐treated compared with untreated men with prostate cancer. The increased risk following various forms of ADT was accounted for mainly by associations with pathologic fractures (14% of all fractures). Among men not on ADT (62% of the cohort), more traditional osteoporosis risk factors were implicated. In both groups, underlying clinical characteristics prompting different treatments (indication bias) may have been partially responsible for the associations seen with specific therapies. To the extent that advanced‐stage disease and pathologic fractures account for the excess risk, the effectiveness of fracture prevention among men with prostate cancer may be limited. © 2011 American Society for Bone and Mineral Research     

Comparative clinical outcomes between pediatric and young adult dialysis patients

Published data on the comparative achievement of The Kidney Disease Dialysis Outcome Quality Initative (KDOQI) recommended clinical performance targets between children and young adults on dialysis are scarce. To characterize the achievement of KDOQI targets among children (<18 years) and young adults (18–24 years) with prevalent end stage renal disease (ESRD), we performed a cross-sectional analysis of data collected by the Mid-Atlantic Renal Coalition, in conjunction with the 2007 and 2008 ESRD Clinical Performance Measures Projects. Data on all enrolled pediatric dialysis patients, categorized into three age groups (0–8, 9–12, 13–17 years), and on a random sample of 5% of patients ≥18 years in ESRD Network 5 were examined for two study periods: hemodialysis (HD) data were collected from October to December 2006 and from October to December 2007 and peritoneal dialysis (PD) data were collected from October 2006 to March 2007 and from October 2007 to March 2008. In total, 114 unique patients were enrolled the study, of whom 41.2% (47/114) were on HD and 58.8% (67/114) on PD. Compared to the pediatric patients, young adults were less likely to achieve the KDOQI recommended serum phosphorus levels and serum calcium × phosphorus product values, with less than one-quarter demonstrating values at or below each goal. Multivariate analysis revealed that both young adults and 13- to 17-year-olds were less likely to achieve target values for phosphorus [young adults: odds ratio (OR) 0.04, 95% confidence interval (95% CI) 0.01–0.19, p < 0.001; 13- to 17-year-olds: OR 0.17, 95% CI 0.04–0.77, p = 0.02] and calcium × phosphorus product (young adults: OR 0.01, 95% CI 0.002–0.09, p <  0.001; 13- to 17-year-olds: OR 0.09, 95% CI 0.02–0.56, p = 0.01) than younger children. In summary, there are significant differences in clinical indices between pediatric and young adult ESRD patients.     

Is vitamin D a determinant of muscle mass and strength?

There remains little consensus on the link between vitamin levels and muscle mass or strength. We therefore investigated the association of serum 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)(2) D), and parathyroid hormone (PTH) levels with skeletal muscle mass and strength. We studied 311 men (mean age, 56 years; range, 23-91 years) and 356 women (mean age, 57 years; range, 21-97 years) representing an age-stratified, random sample of community adults. Multivariate linear regression models were used to examine the association of skeletal muscle mass (by total body dual-energy X-ray absorptiometry) and strength (handgrip force and isometric knee extension moment) with each of 25(OH)D, 1,25(OH)(2) D, and PTH quartiles, adjusted for age, physical activity, fat mass, and season. We found no consistent association between 25(OH)D or PTH and any of our measurements of muscle mass or strength, in either men or women. However, in subjects younger than 65 years, there was a statistically significant association between low 1,25(OH)(2) D levels and low skeletal mass in both men and women and low isometric knee extension moment in women, after adjustment for potential confounders. Modestly low 25(OH)D or high PTH levels may not contribute significantly to sarcopenia or muscle weakness in community adults. The link between low 25(OH)D and increased fall risk reported by others may be due to factors that affect neuromuscular function rather than muscle strength. The association between low 1,25(OH)(2) D and low skeletal mass and low knee extension moment, particularly in younger people, needs further exploration.     

Effects of raloxifene, a selective estrogen receptor modulator, on bone turnover markers and serum sex steroid and lipid levels in elderly men.

Several lines of evidence implicate estrogen deficiency as a cause of bone loss in elderly men. Thus, in 50 elderly men (mean age +/- SD, 69.1 +/- 6.0 years), we performed a randomized blinded study to assess the effect of 6 months of treatment with 60 mg/day of raloxifene (a selective estrogen receptor modulator [SERM] that has an agonist effect on bone but is not feminizing) versus placebo on bone turnover markers. The mean changes in bone turnover markers, serum sex steroid, or lipid levels with treatment did not differ between groups. However, changes in urinary cross-linked N-telopeptide of type I collagen (NTX) excretion were related directly to the baseline serum estradiol level in the raloxifene (r = 0.57; p = 0.004) but not in the placebo-treated (r = 0.15; p = 0.485) men (p = 0.015 for the difference between groups). Moreover, the men in whom NTX excretion decreased after raloxifene treatment had significantly lower baseline estradiol levels (mean +/- SEM, 22 +/- 2 pg/ml) than the men in whom urinary NTX excretion didn't change or increased after raloxifene therapy (30 +/- 3 pg/ml; p = 0.03), and no such difference was found in the placebo group. Thus, raloxifene has no significant effect on bone turnover markers or lipid levels in elderly men. However, the association noted between baseline estradiol levels and the change in urine NTX excretion in the raloxifene-treated men suggests that a subset of men with low estradiol levels may respond to raloxifene or other SERMs, and further studies are needed to directly test this possibility.     

Injuries produced by blunt trauma to the human patellofemoral joint vary with flexion angle of the knee.

Patellofemoral joint impact trauma during car accidents, sporting activities, and falls can produce acute gross fracture of bone, microfracture of bone, and soft tissue injury. Field studies of car accidents, however, show that most patellofemoral traumas are classified as 'subfracture' level injuries. While experimental studies have shown that the influence of flexion angle at impact is not well understood, flexion angle may influence injury location and severity. In the current study, 18 pairs of isolated human cadaver knees were subjected to blunt impact at flexion angles of 60 degrees, 90 degrees, or 120 degrees. One knee from each cadaver was sequentially impacted until gross fracture of bone was produced. The contralateral knee was subjected to a single, subfracture impact at 45% of the impact energy producing fracture in the first knee. The fracture experiments produced gross fracture of the patella and femoral condyles with the fracture plane positioned largely within the region of patellofemoral contact. The fracture location and character changed with flexion angle: at higher flexion angles the proximal pole of the patella and the femoral condyles were more susceptible to injury. For the 90 degrees flexion angle, the patella was fractured centrally, while at 60 degrees the distal pole fractured transversely at the insertion of the patellar tendon. In addition, the load magnitude required to produce fracture increased with flexion angle. In the 'subfracture' knees, injuries were documented for all flexion angles; occult microfractures of the subchondral and trabecular bone and fissures of the articular surface. Similar to the fracture-level experiments, the injuries coincided with the patellofemoral contact region. These data show that knee flexion angle plays an important role in impact related knee trauma. Such data may be useful in the clinical setting, as well as in the design of injury prevention strategies.     

Alpha1-antitrypsin protects beta-cells from apoptosis

Beta-cell apoptosis appears to represent a key event in the pathogenesis of type 1 diabetes. Previous studies have demonstrated that administration of the serine proteinase inhibitor alpha1-antitrypsin (AAT) prevents type 1 diabetes development in NOD mice and prolongs islet allograft survival in rodents; yet the mechanisms underlying this therapeutic benefit remain largely unclear. Herein we describe novel findings indicating that AAT significantly reduces cytokine- and streptozotocin (STZ)-induced beta-cell apoptosis. Specifically, strong antiapoptotic activities for AAT (Prolastin, human) were observed when murine insulinoma cells (MIN6) were exposed to tumor necrosis factor-alpha. In a second model system involving STZ-induced beta-cell apoptosis, treatment of MIN6 cells with AAT similarly induced a significant increase in cellular viability and a reduction in apoptosis. Importantly, in both model systems, treatment with AAT completely abolished induced caspase-3 activity. In terms of its activities in vivo, treatment of C57BL/6 mice with AAT prevented STZ-induced diabetes and, in agreement with the in vitro analyses, supported the concept of a mechanism involving the disruption of beta-cell apoptosis. These results propose a novel biological function for this molecule and suggest it may represent an effective candidate for attempts seeking to prevent or reverse type 1 diabetes.     

Coagulation cascade activation triggers early failure of pig hearts expressing human complement regulatory genes

Abstract: Background: Hyperacute rejection (HAR) and early graft failure (EGF) have been described in a minority of pig‐to‐baboon heart transplants using organs transgenic for human complement regulatory proteins (hCRP). Here we investigate the role of coagulation cascade activation in the pathogenesis of HAR and EGF in a consecutive series where a high incidence of these outcomes was observed. Methods: Twenty‐eight naïve wild‐caught Papio anubis baboons received heterotopic heart transplants from pigs transgenic for hDAF (n = 23) or hMCP (n = 5). Immunosuppression consisted of cyclosporine A, cyclophosphamide and MMF (n = 18) or anti‐CD154 mAb (IDEC‐131) and ATG (n = 10). Eleven received anti‐Gal carbohydrates (GAS914, n = 8, or NEX1285, n = 3), of which four also underwent extracorporeal immunoadsorption (EIA), and 12 also received pharmacologic complement inhibitors (C1 INH, n = 9, or APT070, n = 3). Results: Excluding one technical failure, 14 of 27 transplants (11 hDAF, 3 hMCP) exhibited either HAR (n = 10) or EGF (n = 4). Surprisingly, neither complement inhibition (with C1 INH or APT070) nor anti‐Gal antibody depletion with GAS914, NEX1285, or additional EIA consistently prevented HAR or EGF despite low or undetectable complement deposition. Strikingly, most grafts with HAR/EGF exhibited prominent fibrinogen and platelet deposition associated with systemic coagulation cascade activation, consistent with non‐physiologic intravascular coagulation, in many instances despite little evidence for antibody‐mediated complement activation. Conclusion: We conclude that dysregulated coagulation correlates closely with and probably causes primary failure of pig hearts transgenic for hCRP. These data support efforts to define effective strategies to prevent dysregulated coagulation in pig organ xenografts.     

Structural determinants of vertebral fracture risk.

Vertebral fractures are more strongly associated with specific bone density, structure, and strength parameters than with areal BMD, but all of these variables are correlated. INTRODUCTION: It is unclear whether the association of areal BMD (aBMD) with vertebral fracture risk depends on bone density per se, bone macro- or microstructure, overall bone strength, or spine load/bone strength ratios. MATERIALS AND METHODS: From an age-stratified sample of Rochester, MN, women, we identified 40 with a clinically diagnosed vertebral fracture (confirmed semiquantitatively) caused by moderate trauma (cases; mean age, 78.6 +/- 9.0 yr) and compared them with 40 controls with no osteoporotic fracture (mean age, 70.9 +/- 6.8 yr). Lumbar spine volumetric BMD (vBMD) and geometry were assessed by central QCT, whereas microstructure was evaluated by high-resolution pQCT at the ultradistal radius. Vertebral failure load ( approximately strength) was estimated from voxel-based finite element models, and the factor-of-risk (phi) was determined as the ratio of applied spine loads to failure load. RESULTS: Spine loading (axial compressive force on L3) was similar in vertebral fracture cases and controls (e.g., for 90 degrees forward flexion, 2639 versus 2706 N; age-adjusted p = 0.173). However, fracture cases had inferior values for most bone density and structure variables. Bone strength measures were also reduced, and the factor-of-risk (phi) was 35-37% greater (worse) among women with a vertebral fracture. By age-adjusted logistic regression, relative risks for the strongest fracture predictor in each of the five main variable categories were bone density (total lumbar spine vBMD: OR per SD change, 2.2; 95% CI, 1.1-4.3), bone geometry (vertebral apparent cortical thickness: OR, 2.1; 95% CI, 1.1-4.1), bone microstructure (none significant); bone strength ("cortical" [outer 2 mm] compressive strength: OR, 2.5; 95% CI, 1.3-4.8), and factor-of-risk (phi for 90 degrees forward flexion/overall vertebral compressive strength: OR, 3.2; 95% CI, 1.4-7.5). These variables were correlated with spine aBMD (partial r, -0.32 to 0.75), but each was a stronger predictor of fracture in the logistic regression analyses. CONCLUSIONS: The association of aBMD with vertebral fracture risk is explained by its correlation with more specific bone density, structure, and strength parameters. These may allow deeper insights into fracture pathogenesis.     

Adeno-Associated Viral Vector-Mediated Interleukin-10 Prolongs Allograft Survival in a Rat Kidney Transplantation Model

Interleukin-10 (IL-10) is a pleiotropic cytokine that plays a pivotal role in the regulation of immune responses. Hence, we evaluated the effects of a recombinant adeno-associated viral vector 1 (rAAV1) encoding rat IL-10 (rAAV1-IL-10) in a rat model of kidney allograft rejection. Dark Agouti rat kidneys were transplanted into Wistar-Furth (WF) rats 8 weeks following a single intramuscular administration of either rAAV1-IL-10 or rAAV1-green fluorescence protein (GFP). Isografts (WF-WF) served as an additional experimental control. Both allograft and isograft recipients received daily cyclosporine (10 mg/kg) for 14 days after transplantation. Serum IL-10 levels increased at 8, 12 and 16 weeks following vector administration in rAAV1-IL-10-treated animals, but not in rAAV1-GFP and isograft groups. rAAV1-IL-10 treatment resulted in lower BUN and creatinine levels (p<0.001), as well as increased allograft survival rates from 22% to 90%. Allograft histological abnormalities were significantly attenuated in the rAAV1-IL-10-treated rats compared with those of rAAV1-GFP controls. Serum levels of proinflammatory cytokines such as growth-related oncogene were also significantly higher in the rAAV1-GFP group than in the rAAV1-IL-10 group. These data suggest delivery of IL-10 using a rAAV1 vector improves renal function and prolongs graft survival in a rat model of kidney transplant rejection.     

Grading ovarian serous carcinoma using a two-tier system

In this study, we evaluate a two-tier system for grading ovarian serous carcinoma. This system is based primarily on the assessment of nuclear atypia with the mitotic rate used as a secondary feature. The study included 50 cases of low-grade ovarian serous carcinoma and 50 cases of high-grade ovarian serous carcinoma retrieved from the files of the Department of Pathology at the University of Texas M. D. Anderson Cancer Center from a 28-year period. Cases assigned to the low-grade category were characterized by the presence of mild to moderate nuclear atypia. As a secondary feature, they tended to show up to 12 mitoses per 10 high power fields (HPFs), whereas those in the high-grade category had marked nuclear atypia and as a secondary feature more than 12 mitoses per 10 HPFs. For comparison, the tumors were also graded using the Shimizu/Silverberg and the FIGO grading systems. Patients in the low-grade ovarian serous carcinoma group ranged in age from 19 to 75 years (mean 41.7 years) while patients in the high-grade ovarian serous carcinoma group ranged in age from 27 to 76 years (mean 55 years). All of the cases except one were advanced FIGO stage. Using the Shimizu/Silverberg system, the low-grade ovarian serous carcinoma cases were distributed as follows: grade 1, 47 cases; grade 2, 3 cases. Using the FIGO grading system, 35 cases were grade 1 and 15 cases were grade 2. Regarding the high-grade ovarian serous carcinoma group using the Shimizu/Silverberg system, 14 of the cases were grade 2 and 36 cases were grade 3. Using the FIGO grading system, 1 case was grade 1, 38 cases were grade 2, and 11 cases were grade 3. Most of the patients in both groups were treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy and also received cisplatinum-based chemotherapy. On follow-up, 37 patients in the low-grade ovarian serous carcinoma group had died of disease at a median 4.2 years after diagnosis compared with 46 patients in the high-grade ovarian serous carcinoma group who died of disease at a median of 1.7 years. Eight patients in the low-grade ovarian serous carcinoma group and 4 patients in the high-grade ovarian serous carcinoma group were alive with disease at median follow-ups of 4.3 and 3.85 years, respectively. Four patients with low-grade serous carcinoma were alive without evidence of disease after a follow-up that ranged from 4.4 to 22.6 years (median 6.85 years), and one died of other causes 14 years after the diagnosis of her ovarian tumor. On multivariate analysis, residual tumor and tumor grade based on the M. D. Anderson two-tier system for grading ovarian serous carcinoma were found to be significant independent prognostic factors (P = 0.003 and 0.04, respectively). Of interest, 60% of the low-grade ovarian serous carcinomas in this study were associated with a serous neoplasm of low malignant potential, whereas this association was present in only 2% of the high-grade ovarian serous carcinomas. This finding could reflect a difference in the pathogenesis of ovarian serous carcinomas of different grades. In summary, there is usually a good correlation between the two-tier grading system herein presented and the Shimizu/Silverberg and the FIGO grading systems. Because this system is based on defined criteria that are easy to follow and because it involves only two diagnostic categories, it should provide better reproducibility in the grading of ovarian serous carcinoma. However, additional studies are required to validate these statements.