Updated fracture incidence rates for the US version of FRAX®

# The Author(s) 2009. This article is published with open access at Springerlink.com Summary On the basis of updated fracture and mortality data, we recommend that the base population values used in the US version of FRAX ® be revised. The impact of suggested changes is likely to be a lowering of 10-year fracture probabilities. Introduction Evaluation of results produced by the US version of FRAX ® indicates that this tool overestimates the likelihood of major osteoporotic fracture. In an attempt to correct this, we updated underlying fracture and mortality rates for the model. Methods We used US hospital discharge data from 2006 t

PDEPT: polymer-directed enzyme prodrug therapy

Polymer-directed enzyme prodrug therapy (PDEPT) is a novel two-step antitumour approach using a combination of a polymeric prodrug and polymer-enzyme conjugate to generate cytotoxic drug selectively at the tumour site. In this study the polymeric prodrug N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-Gly-Phe-Leu-Gly-doxorubicin conjugate PK1 (currently under Phase II clinical evaluation) was selected as the model prodrug, and HPMA copolymer-cathepsin B as a model for the activating enzyme conjugate. Following polymer conjugation (yield of 30–35%) HPMA copolymer-cathepsin B retained ~20–25% enzymatic activity in vitro. To investigate pharmacokinetics in vivo,125I-labelled HPMA copolymer-cathepsin B was administered intravenously (i.v.) to B16F10 tumour-bearing mice. HPMA copolymer-cathespin B exhibited a longer plasma half-life (free cathepsin B t1/2α= 2.8 h; bound cathepsin B t1/2α= 3.2 h) and a 4.2-fold increase in tumour accumulation compared to the free enzyme. When PK1 (10 mg kg−1dox-equiv.) was injected i.v. into C57 mice bearing subcutaneously (s.c.) palpable B16F10 tumours followed after 5 h by HPMA copolymer-cathepsin B there was a rapid increase in the rate of dox release within the tumour (3.6-fold increase in the AUC compared to that seen for PK1 alone). When PK1 and the PDEPT combination were used to treat established B16F10 melanoma tumour (single dose; 10 mg kg−1dox-equiv.), the antitumour activity (T/C%) seen for the combination PDEPT was 168% compared to 152% seen for PK1 alone, and 144% for free dox. Also, the PDEPT combination showed activity against a COR-L23 xenograft whereas PK1 did not. PDEPT has certain advantages compared to ADEPT and GDEPT. The relatively short plasma residence time of the polymeric prodrug allows subsequent administration of polymer-enzyme without fear of prodrug activation in the circulation and polymer-enzyme conjugates have reduced immunogenicity. This study proves the concept of PDEPT and further optimisation is warranted. © 2001 Cancer Research Campaign   http://www.bjcancer.co

Effectiveness of bisphosphonates on nonvertebral and hip fractures in the first year of therapy: The risedronate and alendronate (REAL) cohort study

INTRODUCTION: Randomized clinical trials have shown that risedronate and alendronate reduce fractures among women with osteoporosis. The aim of this observational study was to observe, in clinical practice, the incidence of hip and nonvertebral fractures among women in the year following initiation of once-a-week dosing of either risedronate or alendronate. METHODS: Using records of health service utilization from July 2002 through September 2004, we created two cohorts: women (ages 65 and over) receiving risedronate (n = 12,215) or alendronate (n = 21,615). Cox proportional hazard modeling was used to compare the annual incidence of nonvertebral fractures and of hip fractures between cohorts, adjusting for potential differences in risk factors for fractures. RESULTS: There were 507 nonvertebral fractures and 109 hip fractures. Through one year of therapy, the incidence of nonvertebral fractures in the risedronate cohort (2.0%) was 18% lower (95% CI 2% – 32%) than in the alendronate cohort (2.3%). The incidence of hip fractures in the risedronate cohort (0.4%) was 43% lower (95% CI 13% – 63%) than in the alendronate cohort (0.6%). These results were consistent across a number of sensitivity analyses. CONCLUSION: Patients receiving risedronate have lower rates of hip and nonvertebral fractures during their first year of therapy than patients receiving alendronate

FRAX™ and the assessment of fracture probability in men and women from the UK

SUMMARY: A fracture risk assessment tool (FRAX) is developed based on the use of clinical risk factors with or without bone mineral density tests applied to the UK. INTRODUCTION: The aim of this study was to apply an assessment tool for the prediction of fracture in men and women with the use of clinical risk factors (CRFs) for fracture with and without the use of femoral neck bone mineral density (BMD). The clinical risk factors, identified from previous meta-analyses, comprised body mass index (BMI, as a continuous variable), a prior history of fracture, a parental history of hip fracture, use of oral glucocorticoids, rheumatoid arthritis and other secondary causes of osteoporosis, current smoking, and alcohol intake 3 or more units daily. METHODS: Four models were constructed to compute fracture probabilities based on the epidemiology of fracture in the UK. The models comprised the ten-year probability of hip fracture, with and without femoral neck BMD, and the ten-year probability of a major osteoporotic fracture, with and without BMD. For each model fracture and death hazards were computed as continuous functions. RESULTS: Each clinical risk factor contributed to fracture probability. In the absence of BMD, hip fracture probability in women with a fixed BMI (25 kg/m(2)) ranged from 0.2% at the age of 50 years for women without CRF's to 22% at the age of 80 years with a parental history of hip fracture (approximately 100-fold range). In men, the probabilities were lower, as was the range (0.1 to 11% in the examples above). For a major osteoporotic fracture the probabilities ranged from 3.5% to 31% in women, and from 2.8% to 15% in men in the example above. The presence of one or more risk factors increased probabilities in an incremental manner. The differences in probabilities between men and women were comparable at any given T-score and age, except in the elderly where probabilities were higher in women than in men due to the higher mortality of the latter. CONCLUSION: The models provide a framework which enhances the assessment of fracture risk in both men and women by the integration of clinical risk factors alone and/or in combination with BMD

Leucine-Rich Repeat Kinase 2 Modulates Retinoic Acid-Induced Neuronal Differentiation of Murine Embryonic Stem Cells

Background: Dominant mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most prevalent cause of Parkinson’s disease, however, little is known about the biological function of LRRK2 protein. LRRK2 is expressed in neural precursor cells suggesting a role in neurodevelopment. Methodology/Principal Findings: In the present study, differential gene expression profiling revealed a faster silencing of pluripotency-associated genes, like Nanog, Oct4, and Lin28, during retinoic acid-induced neuronal differentiation of LRRK2deficient mouse embryonic stem cells compared to wildtype cultures. By contrast, expression of neurotransmitter receptors and neurotransmitter release was increased in LRRK2+/2 cultures indicating that LRRK2 promotes neuronal differentiation. Consistently, the number of neural progenitor cells was higher in the hippocampal dentate gyrus of adult LRRK2-deficient mice. Alterations in phosphorylation of the putative LRRK2 substrates, translation initiation factor 4E binding protein 1 and moesin, do not appear to be involved in altered differentiation, rather there is indirect evidence that a regulatory signaling network comprising retinoic acid receptors, let-7 miRNA and downstream target genes/mRNAs may be affected in LRRK2deficient stem cells in culture. Conclusion/Significance: Parkinson’s disease-linked LRRK2 mutations that associated with enhanced kinase activity may affect retinoic acid receptor signaling during neurodevelopment and/or neuronal maintenance as has been shown in othe

Beringian Standstill and Spread of Native American Founders

Native Americans derive from a small number of Asian founders who likely arrived to the Americas via Beringia. However, additional details about the intial colonization of the Americas remain unclear. To investigate the pioneering phase in the Americas we analyzed a total of 623 complete mtDNAs from the Americas and Asia, including 20 new complete mtDNAs from the Americas and seven from Asia. This sequence data was used to direct high-resolution genotyping from 20 American and 26 Asian populations. Here we describe more genetic diversity within the founder population than was previously reported. The newly resolved phylogenetic structure suggests that ancestors of Native Americans paused when they reached Beringia, during which time New World founder lineages differentiated from their Asian sister-clades. This pause in movement was followed by a swift migration southward that distributed the founder types all the way to South America. The data also suggest more recent bi-directional gene flow between Siberia and the North American Arctic

Bone Loss in Diabetes: Use of Antidiabetic Thiazolidinediones and Secondary Osteoporosis

Clinical evidence indicates that bone status is affected in patients with type 2 diabetes mellitus (T2DM). Regardless of normal or even high bone mineral density, T2DM patients have increased risk of fractures. One class of antidiabetic drugs, thiazolidinediones (TZDs), causes bone loss and further increases facture risk, placing TZDs in the category of drugs causing secondary osteoporosis. Risk factors for development of TZD-induced secondary osteoporosis are gender (women), age (elderly), and duration of treatment. TZDs exert their antidiabetic effects by activating peroxisome proliferator-activated receptor-γ (PPAR-γ) nuclear receptor, which controls glucose and fatty acid metabolism. In bone, PPAR-γ controls differentiation of cells of mesenchymal and hematopoietic lineages. PPAR-γ activation with TZDs leads to unbalanced bone remodeling: bone resorption increases and bone formation decreases. Laboratory research evidence points toward a possible separation of unwanted effects of PPAR-γ on bone from its beneficial antidiabetic effects by using selective PPAR-γ modulators. This review also discusses potential pharmacologic means to protect bone from detrimental effects of clinically used TZDs (pioglitazone and rosiglitazone) by using combinational therapy with approved antiosteoporotic drugs, or by using lower doses of TZDs in combination with other antidiabetic therapy. We also suggest a possible orthopedic complication, not yet supported by clinical studies, of delayed fracture healing in T2DM patients on TZD therapy

Discovering Dysfunction of Multiple MicroRNAs Cooperation in Disease by a Conserved MicroRNA Co-Expression Network

MicroRNAs, a new class of key regulators of gene expression, have been shown to be involved in diverse biological processes and linked to many human diseases. To elucidate miRNA function from a global perspective, we constructed a conserved miRNA co-expression network by integrating multiple human and mouse miRNA expression data. We found that these conserved co-expressed miRNA pairs tend to reside in close genomic proximity, belong to common families, share common transcription factors, and regulate common biological processes by targeting common components of those processes based on miRNA targets and miRNA knockout/transfection expression data, suggesting their strong functional associations. We also identified several co-expressed miRNA sub-networks. Our analysis reveals that many miRNAs in the same sub-network are associated with the same diseases. By mapping known disease miRNAs to the network, we identified three cancer-related miRNA sub-networks. Functional analyses based on targets and miRNA knockout/transfection data consistently show that these sub-networks are significantly involved in cancer-related biological processes, such as apoptosis and cell cycle. Our results imply that multiple co-expressed miRNAs can cooperatively regulate a given biological process by targeting common components of that process, and the pathogenesis of disease may be associated with the abnormality of multiple functionally cooperative miRNAs rather than individual miRNAs. In addition, many of these co-expression relationships provide strong evidence for the involvement of new miRNAs in important biological processes, such as apoptosis, differentiation and cell cycle, indicating their potential disease links

Xpf and Not the Fanconi Anaemia Proteins or Rev3 Accounts for the Extreme Resistance to Cisplatin in Dictyostelium discoideum

Organisms like Dictyostelium discoideum, often referred to as DNA damage “extremophiles”, can survive exposure to extremely high doses of radiation and DNA crosslinking agents. These agents form highly toxic DNA crosslinks that cause extensive DNA damage. However, little is known about how Dictyostelium and the other “extremophiles” can tolerate and repair such large numbers of DNA crosslinks. Here we describe a comprehensive genetic analysis of crosslink repair in Dictyostelium discoideum. We analyse three gene groups that are crucial for a replication-coupled repair process that removes DNA crosslinks in higher eukarya: The Fanconi anaemia pathway (FA), translesion synthesis (TLS), and nucleotide excision repair. Gene disruption studies unexpectedly reveal that the FA genes and the TLS enzyme Rev3 play minor roles in tolerance to crosslinks in Dictyostelium. However, disruption of the Xpf nuclease subcomponent results in striking hypersensitivity to crosslinks. Genetic interaction studies reveal that although Xpf functions with FA and TLS gene products, most Xpf mediated repair is independent of these two gene groups. These results suggest that Dictyostelium utilises a distinct Xpf nuclease-mediated repair process to remove crosslinked DNA. Other DNA damage–resistant organisms and chemoresistant cancer cells might adopt a similar strategy to develop resistance to DNA crosslinking agents