Forearm bone mineral density and fracture incidence in postmenopausal women with osteoporosis: results from the ACTIVExtend phase 3 trial.

Abaloparatide increased ultradistal radius bone mineral density (BMD) in the Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) trial. Over the subsequent 24 months in ACTIVExtend, ultradistal radius BMD gains were maintained with alendronate. Conversely, 1/3 radius BMD remained stable during ALN treatment in ACTIVExtend after decreasing during ACTIVE. INTRODUCTION: Abaloparatide (ABL) increased femoral neck, total hip, and lumbar spine bone mineral density (BMD) in postmenopausal women with osteoporosis and decreased the risk of vertebral and nonvertebral fractures in ACTIVE. Effects on fracture risk and BMD were maintained subsequently with alendronate (ALN) in ACTIVExtend. In a prespecified subanalysis of ACTIVE, ABL also increased BMD at the ultradistal radius. Our objective was to determine the efficacy of ABL followed by ALN vs placebo (PBO) followed by ALN on forearm BMD and fracture risk over 43 months in ACTIVExtend. METHODS: Ultradistal and 1/3 radius BMD (ACTIVE baseline to month 43) were measured (ABL/ALN, n = 213; PBO/ALN, n = 233). Wrist fracture rates were estimated for the ACTIVExtend intent-to-treat population (ABL/ALN, n = 558; PBO/ALN, n = 581) by Kaplan-Meier (KM) method. RESULTS: At cumulative month 25, mean increase from ACTIVE baseline in ultradistal radius BMD was 1.1% (standard error, 0.49%) with ABL/ALN vs - 0.8% (0.43%) with PBO/ALN (P < 0.01). BMD increases with ABL were maintained with ALN through month 43 in ACTIVExtend. BMD decreases at the 1/3 radius in ACTIVE (similar with ABL and PBO) were maintained through 24 months of ALN treatment in ACTIVExtend. Wrist fractures over 43 months occurred in 15 women with ABL/ALN (KM estimate, 2.8%) and 20 with PBO/ALN (KM estimate, 3.6%) (HR = 0.77, 95% CI 0.39, 1.50; P = not significant). CONCLUSION: Ultradistal radius BMD gains following treatment with ABL in ACTIVE were maintained over 24 months of ALN treatment in ACTIVExtend. Conversely, 1/3 radius BMD remained stable during ALN treatment in ACTIVExtend after decreasing during ACTIVE. TRIAL REGISTRATION: ClinicalTrials.gov : NCT01657162 submitted July 31, 2012.

Correction to: Abaloparatide effect on forearm bone mineral density and wrist fracture risk in postmenopausal women with osteoporosis.

The original version of this article, published on 21 March 2019, unfortunately contains some typos in Figs. 2, 3, 4, and Supplemental Fig. 1. The corrected figures are given below.

Correction to: Abaloparatide effect on forearm bone mineral density and wrist fracture risk in postmenopausal women with osteoporosis.

The original version of this article, published on 21 March 2019, unfortunately contained a mistake.

Factors associated with the contemplative stage of readiness to initiate osteoporosis treatment.

We investigated the factors associated with readiness for initiating osteoporosis treatment in women at high risk of fracture. We found that women in the contemplative stage were more likely to report previously being told having osteoporosis or osteopenia, acknowledge concern about osteoporosis, and disclose prior osteoporosis treatment. INTRODUCTION: Understanding factors associated with reaching the contemplative stage of readiness to initiate osteoporosis treatment may inform the design of behavioral interventions to improve osteoporosis treatment uptake in women at high risk for fracture. METHODS: We measured readiness to initiate osteoporosis treatment using a modified form of the Weinstein Precaution Adoption Process Model (PAPM) among 2684 women at high risk of fracture from the Activating Patients at Risk for OsteoPOroSis (APROPOS) clinical trial. Pre-contemplative participants were those who self-classified in the unaware and unengaged stages of PAPM (stages 1 and 2). Contemplative participants were those in the undecided, decided not to act, or decided to act stages of PAPM (stages 3, 4, and 5). Using multivariable logistic regression, we evaluated participant characteristics associated with levels of readiness to initiate osteoporosis treatment. RESULTS: Overall, 24% (N = 412) self-classified in the contemplative stage of readiness to initiate osteoporosis treatment. After adjusting for age, race, education, health literacy, and major osteoporotic fracture in the past 12 months, contemplative women were more likely to report previously being told they had osteoporosis or osteopenia (adjusted odds ratio [aOR] (95% CI) 11.8 (7.8-17.9) and 3.8 (2.5-5.6), respectively), acknowledge concern about osteoporosis (aOR 3.5 (2.5-4.9)), and disclose prior osteoporosis treatment (aOR 4.5 (3.3-6.3)) than women who self-classified as pre-contemplative. CONCLUSIONS: For women at high risk for future fractures, ensuring women's recognition of their diagnosis of osteoporosis/osteopenia and addressing their concerns about osteoporosis are critical components to consider when attempting to influence stage of behavior transitions in osteoporosis treatment.

Abaloparatide effect on forearm bone mineral density and wrist fracture risk in postmenopausal women with osteoporosis.

PURPOSE: Wrist fractures are common, contribute significantly to morbidity in women with postmenopausal osteoporosis, and occur predominantly at the ultradistal radius, a site rich in trabecular bone. This exploratory analysis of the phase 3 ACTIVE study evaluated effects of abaloparatide versus placebo and teriparatide on forearm bone mineral density (BMD) and risk of wrist fracture. METHODS: Forearm BMD was measured by dual energy X-ray absorptiometry in a subset of 982 women from ACTIVE, evenly distributed across the three treatment groups. Wrist fractures were ascertained in the total cohort (N = 2463). RESULTS: After 18 months, ultradistal radius BMD changes from baseline were 2.25 percentage points greater for abaloparatide compared with placebo (95% confidence interval (CI) 1.38, 3.12, p < 0.001) and 1.54 percentage points greater for abaloparatide compared with teriparatide (95% CI 0.64, 2.45, p < 0.001). At 18 months, 1/3 radius BMD losses (versus baseline) were similar for abaloparatide compared with placebo (-0.42; 95% CI -1.03, 0.20; p = 0.19) but losses with teriparatide exceeded those of placebo (-1.66%; 95% CI -2.27, -1.06; p < 0.001). The decline with abaloparatide was less than that seen with teriparatide (group difference 1.22%; 95% CI 0.57, 1.87; p < 0.001). The radius BMD findings, at both ultradistal and 1/3 sites, are consistent with the numerically lower incidence of wrist fractures observed in women treated with abaloparatide compared with teriparatide (HR = 0.43; 95% CI 0.18, 1.03; p = 0.052) and placebo (HR = 0.49, 95% CI 0.20, 1.19, p = 0.11). CONCLUSIONS: Compared with teriparatide, abaloparatide increased BMD at the ultradistal radius (primarily trabecular bone) and decreased BMD to a lesser extent at the 1/3 radius (primarily cortical bone), likely contributing to the numerically lower wrist fracture incidence observed with abaloparatide.

Evidence for newly generated interneurons in the basolateral amygdala of adult mice.

New neurons are continually generated from the resident populations of precursor cells in selective niches of the adult mammalian brain such as the hippocampal dentate gyrus and the olfactory bulb. However, whether such cells are present in the adult amygdala, and their neurogenic capacity, is not known. Using the neurosphere assay, we demonstrate that a small number of precursor cells, the majority of which express Achaete-scute complex homolog 1 (Ascl1), are present in the basolateral amygdala (BLA) of the adult mouse. Using neuron-specific Thy1-YFP transgenic mice, we show that YFP+ cells in BLA-derived neurospheres have a neuronal morphology, co-express the neuronal marker ßIII-tubulin, and generate action potentials, confirming their neuronal phenotype. In vivo, we demonstrate the presence of newly generated BrdU-labeled cells in the adult BLA, and show that a proportion of these cells co-express the immature neuronal marker doublecortin (DCX). Furthermore, we reveal that a significant proportion of GFP+ neurons (~23%) in the BLA are newly generated (BrdU+) in DCX-GFP mice, and using whole-cell recordings in acute slices we demonstrate that the GFP+ cells display electrophysiological properties that are characteristic of interneurons. Using retrovirus-GFP labeling as well as the Ascl1CreERT2 mouse line, we further confirm that the precursor cells within the BLA give rise to mature and functional interneurons that persist in the BLA for at least 8 weeks after their birth. Contextual fear conditioning has no effect on the number of neurospheres or BrdU-labeled cells in the BLA, but produces an increase in hippocampal cell proliferation. These results demonstrate that neurogenic precursor cells are present in the adult BLA, and generate functional interneurons, but also show that their activity is not regulated by an amygdala-dependent learning paradigm.

Adverse bone effects of medications used to treat non-skeletal disorders.

There is a growing list of medications used to treat non-skeletal disorders that cause bone loss and/or increase fracture risk. This review discusses glucocorticoids, drugs that reduce sex steroids, antidiabetic agents, acid-reducing drugs, selective serotonin reuptake inhibitors, and heparin. A number of drugs are known to cause bone loss, increase fracture risk, or both. These drugs should be used in the lowest dose necessary to achieve the desired benefit and for the shortest time necessary, but in many cases, long-term treatment is required. Effective countermeasures are available for some.

Self-perception of fracture risk: what can it tell us?

In this study, we report that self-perception of fracture risk captures some aspect of fracture risk not currently measured using conventional fracture prediction tools and is associated with improved medication uptake. It suggests that adequate appreciation of fracture risk may be beneficial and lead to greater healthcare engagement and treatment. INTRODUCTION: This study aimed to assess how well self-perception of fracture risk, and fracture risk as estimated by the fracture prediction tool FRAX, related to fracture incidence and uptake and persistence of anti-osteoporosis medication among women participating in the Global Longitudinal study of Osteoporosis in Women (GLOW). METHODS: GLOW is an international cohort study involving 723 physician practices across 10 countries in Europe, North America and Australia. Aged ≥ 55 years, 60,393 women completed baseline questionnaires detailing medical history, including co-morbidities, fractures and self-perceived fracture risk (SPR). Annual follow-up included self-reported incident fractures and anti-osteoporosis medication (AOM) use. We calculated FRAX risk without bone mineral density measurement. RESULTS: Of the 39,241 women with at least 1 year of follow-up data, 2132 (5.4%) sustained an incident major osteoporotic fracture over 5 years of follow-up. Within each SPR category, risk of fracture increased as the FRAX categorisation of risk increased. In GLOW, only 11% of women with a lower baseline SPR were taking AOM at baseline, compared with 46% of women with a higher SPR. AOM use tended to increase in the years after a reported fracture. However, women with a lower SPR who were fractured still reported lower AOM rates than women with or without a fracture but had a higher SPR. CONCLUSIONS: These results suggest that SPR captures some aspect of fracture risk not currently measured using conventional fracture prediction tools and is also associated with improved medication uptake.

This baby is not for turning: Women's experiences of attempted external cephalic version.

BACKGROUND: Existing studies regarding women's experiences surrounding an External Cephalic Version (ECV) report on women who have a persistent breech post ECV and give birth by caesarean section, or on women who had successful ECVs and plan for a vaginal birth. There is a paucity of understanding about the experience of women who attempt an ECV then plan a vaginal breech birth when their baby remains breech. The aim of this study was to examine women's experience of an ECV which resulted in a persistent breech presentation. METHODS: A qualitative descriptive exploratory design was undertaken. In-depth semi-structured interviews were conducted and analysed thematically. RESULTS: Twenty two (n = 22) women who attempted an ECV and subsequently planned a vaginal breech birth participated. Twelve women had a vaginal breech birth (55 %) and 10 (45 %) gave birth by caesarean section. In relation to the ECV, there were five main themes identified: 'seeking an alternative', 'needing information', 'recounting the ECV experience', 'reacting to the unsuccessful ECV' and, 'reflecting on the value of an ECV'. CONCLUSIONS: ECV should form part of a range of options provided to women, rather than a default procedure for management of the term breech. For motivated women who fit the safe criteria for vaginal breech birth, not being subjected to a painful experience (ECV) may be optimal. Women should be supported to access services that support vaginal breech birth if this is their choice, and continuity of care should be standard practice.

Taxonomy of rare genetic metabolic bone disorders.

UNLABELLED: This article reports a taxonomic classification of rare skeletal diseases based on metabolic phenotypes. It was prepared by The Skeletal Rare Diseases Working Group of the International Osteoporosis Foundation (IOF) and includes 116 OMIM phenotypes with 86 affected genes. INTRODUCTION: Rare skeletal metabolic diseases comprise a group of diseases commonly associated with severe clinical consequences. In recent years, the description of the clinical phenotypes and radiographic features of several genetic bone disorders was paralleled by the discovery of key molecular pathways involved in the regulation of bone and mineral metabolism. Including this information in the description and classification of rare skeletal diseases may improve the recognition and management of affected patients. METHODS: IOF recognized this need and formed a Skeletal Rare Diseases Working Group (SRD-WG) of basic and clinical scientists who developed a taxonomy of rare skeletal diseases based on their metabolic pathogenesis. RESULTS: This taxonomy of rare genetic metabolic bone disorders (RGMBDs) comprises 116 OMIM phenotypes, with 86 affected genes related to bone and mineral homeostasis. The diseases were divided into four major groups, namely, disorders due to altered osteoclast, osteoblast, or osteocyte activity; disorders due to altered bone matrix proteins; disorders due to altered bone microenvironmental regulators; and disorders due to deranged calciotropic hormonal activity. CONCLUSIONS: This article provides the first comprehensive taxonomy of rare metabolic skeletal diseases based on deranged metabolic activity. This classification will help in the development of common and shared diagnostic and therapeutic pathways for these patients and also in the creation of international registries of rare skeletal diseases, the first step for the development of genetic tests based on next generation sequencing and for performing large intervention trials to assess efficacy of orphan drugs.

The clinical diagnosis of osteoporosis: a position statement from the National Bone Health Alliance Working Group.

UNLABELLED: Osteoporosis causes an elevated fracture risk. We propose the continued use of T-scores as one means for diagnosis but recommend that, alternatively, hip fracture; osteopenia-associated vertebral, proximal humerus, pelvis, or some wrist fractures; or FRAX scores with ≥3% (hip) or 20% (major) 10-year fracture risk also confer an osteoporosis diagnosis. INTRODUCTION: Osteoporosis is a common disorder of reduced bone strength that predisposes to an increased risk for fractures in older individuals. In the USA, the standard criterion for the diagnosis of osteoporosis in postmenopausal women and older men is a T-score of ≤ -2.5 at the lumbar spine, femur neck, or total hip by bone mineral density testing. METHODS: Under the direction of the National Bone Health Alliance, 17 clinicians and clinical scientists were appointed to a working group charged to determine the appropriate expansion of the criteria by which osteoporosis can be diagnosed. RESULTS: The group recommends that postmenopausal women and men aged 50 years should be diagnosed with osteoporosis if they have a demonstrable elevated risk for future fractures. This includes having a T-score of less than or equal to -2.5 at the spine or hip as one method for diagnosis but also permits a diagnosis for individuals in this population who have experienced a hip fracture with or without bone mineral density (BMD) testing and for those who have osteopenia by BMD who sustain a vertebral, proximal humeral, pelvic, or, in some cases, distal forearm fracture. Finally, the term osteoporosis should be used to diagnose individuals with an elevated fracture risk based on the World Health Organization Fracture Risk Algorithm, FRAX. CONCLUSIONS: As new ICD-10 codes become available, it is our hope that this new understanding of what osteoporosis represents will allow for an appropriate diagnosis when older individuals are recognized as being at an elevated risk for fracture.

Disease-specific perception of fracture risk and incident fracture rates: GLOW cohort study.

UNLABELLED: Accurate patient risk perception of adverse health events promotes greater autonomy over, and motivation towards, health-related lifestyles. INTRODUCTION: We compared self-perceived fracture risk and 3-year incident fracture rates in postmenopausal women with a range of morbidities in the Global Longitudinal study of Osteoporosis in Women (GLOW). METHODS: GLOW is an international cohort study involving 723 physician practices across ten countries (Europe, North America, Australasia); 60,393 women aged ≥55 years completed baseline questionnaires detailing medical history and self-perceived fracture risk. Annual follow-up determined self-reported incident fractures. RESULTS: In total 2,945/43,832 (6.8%) sustained an incident fracture over 3 years. All morbidities were associated with increased fracture rates, particularly Parkinson's disease (hazard ratio [HR]; 95% confidence interval [CI], 3.89; 2.78-5.44), multiple sclerosis (2.70; 1.90-3.83), cerebrovascular events (2.02; 1.67-2.46), and rheumatoid arthritis (2.15; 1.53-3.04) (all p < 0.001). Most individuals perceived their fracture risk as similar to (46%) or lower than (36%) women of the same age. While increased self-perceived fracture risk was strongly associated with incident fracture rates, only 29% experiencing a fracture perceived their risk as increased. Under-appreciation of fracture risk occurred for all morbidities, including neurological disease, where women with low self-perceived fracture risk had a fracture HR 2.39 (CI 1.74-3.29) compared with women without morbidities. CONCLUSIONS: Postmenopausal women with morbidities tend to under-appreciate their risk, including in the context of neurological diseases, where fracture rates were highest in this cohort. This has important implications for health education, particularly among women with Parkinson's disease, multiple sclerosis, or cerebrovascular disease.

Effectiveness of risedronate and alendronate on nonvertebral fractures: an observational study through 2 years of therapy.

UNLABELLED: This observational study showed that after 2 years, both risedronate and alendronate lowered the risk of hip and nonvertebral fractures compared with patients filling in a single bisphosphonate prescription. INTRODUCTION: Post hoc analyses of the placebo-controlled trials suggested earlier effects for risedronate (6-12 months) than for alendronate (18-24 months). The present study extends our 1-year observational data that confirmed an earlier fracture reduction with risedronate and evaluated the absolute and relative effectiveness of alendronate and risedronate in clinical practice over 2 years. METHODS: We observed three cohorts of women aged 65 years and older who initiated once-a-week dosing of bisphosphonate therapy; (1) patients adherent to alendronate (n = 21,615), (2) patients adherent to risedronate (n = 12,215), or (3) patients filling only a single bisphosphonate prescription (n = 5,390) as a referent population. Proportional hazard modeling compared the incidence of hip and nonvertebral fractures among the cohorts over 2 years after the initial prescription. RESULTS: In this cohort, we previously showed at 12 months a significant reduction of hip and nonvertebral fractures with risedronate but not with alendronate. At the end of 2 years, the cumulative incidence of hip fractures in the referent cohort was 1.9 %, and incidence of nonvertebral fractures was 6.3 %. Relative to the referent, 6 months after initiating therapy and continuing through 2 years, both risedronate and alendronate cohorts had approximately a 45 % lower incidence of hip fractures and a 30 % lower incidence of nonvertebral fractures. CONCLUSION: These observations suggest that both risedronate and alendronate are effective at reducing the risk of hip and nonvertebral fracture after 2 years of treatment and support the post hoc analyses of placebo-controlled trials indicating an earlier effect of risedronate.

Non-hip, non-spine fractures drive healthcare utilization following a fracture: the Global Longitudinal Study of Osteoporosis in Women (GLOW).

UNLABELLED: We evaluated healthcare utilization associated with treating fracture types in >51,000 women aged ≥55 years. Over the course of 1 year, there were five times more non-hip, non-spine fractures than hip or spine fractures, resulting in twice as many days of hospitalization and rehabilitation/nursing home care for non-hip, non-spine fractures. INTRODUCTION: The purpose of this study is to evaluate medical healthcare utilization associated with treating several types of fractures in women ≥55 years from various geographic regions. METHODS: Information from the Global Longitudinal Study of Osteoporosis in Women (GLOW) was collected via self-administered patient questionnaires at baseline and year 1 (n = 51,491). Self-reported clinically recognized low-trauma fractures at year 1 were classified as incident spine, hip, wrist/hand, arm/shoulder, pelvis, rib, leg, and other fractures. Healthcare utilization data were self-reported and included whether the fracture was treated at a doctor's office/clinic or at a hospital. Patients were asked if they had undergone surgery or been treated at a rehabilitation center or nursing home. RESULTS: During 1-year follow-up, there were 195 spine, 134 hip, and 1,654 non-hip, non-spine fractures. Clinical vertebral fractures resulted in 617 days of hospitalization and 512 days of rehabilitation/nursing home care; hip fractures accounted for 1,306 days of hospitalization and 1,650 days of rehabilitation/nursing home care. Non-hip, non-spine fractures resulted in 3,805 days in hospital and 5,186 days of rehabilitation/nursing home care. CONCLUSIONS: While hip and vertebral fractures are well recognized for their associated increase in health resource utilization, non-hip, non-spine fractures, by virtue of their 5-fold greater number, require significantly more healthcare resources.

Infections in postmenopausal women with osteoporosis treated with denosumab or placebo: coincidence or causal association?

UNLABELLED: Serious adverse events of infections that occurred in subjects receiving denosumab or placebo in the Fracture Reduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) study were examined in detail. Serious adverse events of infections in denosumab subjects had heterogeneous etiology, with no clear clinical pattern to suggest a relationship to time or duration of exposure to denosumab. INTRODUCTION: Denosumab reduces the risk for new vertebral, hip, and nonvertebral fractures compared with placebo. In the pivotal phase 3 fracture trial (FREEDOM), the overall safety profile and incidence of adverse events including adverse events of infections were similar between groups. Serious adverse events of erysipelas and cellulitis were more frequent in denosumab-treated subjects. In this report, we further evaluate the details of infectious events in FREEDOM to better understand if RANKL inhibition with denosumab influences infection risk. METHODS: FREEDOM was an international multicenter, randomized, double-blind, placebo-controlled study in postmenopausal women with osteoporosis randomly assigned to receive placebo (n = 3,906) or denosumab 60 mg every 6 months (n = 3,902). The incidence of adverse events and serious adverse events categorized within the Medical Dictionary for Regulatory Activities system organ class, "Infections and Infestations," was compared between the placebo and denosumab groups by body systems and preferred terms. The temporal relationship between occurrence of serious adverse events of infections of interest and administration of denosumab was explored. RESULTS: Serious adverse events of infections involving the gastrointestinal system, renal and urinary system, ear, and endocarditis were numerically higher in the denosumab group compared with placebo, but the number of events was small. No relationship was observed between serious adverse events of infections and timing of administration or duration of exposure to denosumab. CONCLUSIONS: Serious adverse events of infections that occurred with denosumab treatment had heterogeneous etiology, with no clear clinical pattern to suggest a relationship to time or duration of exposure to denosumab.

Regional and age-related variations in the proportions of hip fractures and major fractures among postmenopausal women: the Global Longitudinal Study of Osteoporosis in Women.

UNLABELLED: We examined variations in proportions of hip fractures and major fractures among postmenopausal women using the Global Longitudinal Study of Osteoporosis in Women (GLOW). The proportion of major fractures that were hip fractures varied with age and region, whereas variations in the proportion of fractures that were major fractures appeared modest. INTRODUCTION: In many countries, the World Health Organization fracture risk assessment tool calculates the probability of major fractures by assuming a uniform age-associated proportion of major fractures that are hip fractures in different countries. We further explored this assumption, using data from the GLOW. METHODS: GLOW is an observational population-based study of 60,393 non-institutionalized women aged ≥55 years who had visited practices within the previous 2 years. Main outcome measures were self-reported prevalent fractures after the age of 45 years and incident fractures during the 2 years of follow-up. RESULTS: The adjusted proportion of prevalent and incident major fractures after the age of 45 years that were hip fractures was higher in North America (16%, 17%) than in northern (13%, 12%) and southern Europe (10%, 10%), respectively. The proportion of incident major fractures that were hip fractures increased more than five-fold with age, from 6.6% among 55-59-year-olds to 34% among those aged ≥85 years. Regional and age-associated variations in the proportion of all incident fractures that were major fractures were less marked, not exceeding 16% and 28%, respectively. CONCLUSIONS: The data suggest that there may be regional differences in the proportion of major fractures that are hip fractures in postmenopausal women. In contrast, the regional and age-related variations in the proportion of fractures that are major fractures appear to be modest. However, because of the limited number of fractures in our sample, further studies are necessary to confirm these findings.

Burden of non-hip, non-vertebral fractures on quality of life in postmenopausal women: the Global Longitudinal study of Osteoporosis in Women (GLOW).

UNLABELLED: Among 50,461 postmenopausal women, 1,822 fractures occurred (57% minor non-hip, non-vertebral [NHNV], 26% major NHNV, 10% spine, 7% hip) over 1 year. Spine fractures had the greatest detrimental effect on EQ-5D, followed by major NHNV and hip fractures. Decreases in physical function and health status were greatest for spine or hip fractures. INTRODUCTION: There is growing evidence that NHNV fractures result in substantial morbidity and healthcare costs. The aim of this prospective study was to assess the effect of these NHNV fractures on quality of life. METHODS: We analyzed the 1-year incidences of hip, spine, major NHNV (pelvis/leg, shoulder/arm) and minor NHNV (wrist/hand, ankle/foot, rib/clavicle) fractures among women from the Global Longitudinal study of Osteoporosis in Women (GLOW). Health-related quality of life (HRQL) was analyzed using the EuroQol EQ-5D tool and the SF-36 health survey. RESULTS: Among 50,461 women analyzed, there were 1,822 fractures (57% minor NHNV, 26% major NHNV, 10% spine, 7% hip) over 1 year. Spine fractures had the greatest detrimental effect on EQ-5D summary scores, followed by major NHNV and hip fractures. The number of women with mobility problems increased most for those with major NHNV and spine fractures (both +8%); spine fractures were associated with the largest increases in problems with self care (+11%), activities (+14%), and pain/discomfort (+12%). Decreases in physical function and health status were greatest for those with spine or hip fractures. Multivariable modeling found that EQ-5D reduction was greatest for spine fractures, followed by hip and major/minor NHNV. Statistically significant reductions in SF-36 physical function were found for spine fractures, and were borderline significant for major NHNV fractures. CONCLUSION: This prospective study shows that NHNV fractures have a detrimental effect on HRQL. Efforts to optimize the care of osteoporosis patients should include the prevention of NHNV fractures.

Failure to perceive increased risk of fracture in women 55 years and older: the Global Longitudinal Study of Osteoporosis in Women (GLOW).

UNLABELLED: We compared self-perception of fracture risk with actual risk among 60,393 postmenopausal women aged ≥55 years, using data from the Global Longitudinal Study of Osteoporosis in Women (GLOW). Most postmenopausal women with risk factors failed to appreciate their actual risk for fracture. Improved education about osteoporosis risk factors is needed. INTRODUCTION: This study seeks to compare self-perception of fracture risk with actual risk among postmenopausal women using data from GLOW. METHODS: GLOW is an international, observational, cohort study involving 723 physician practices in 17 sites in ten countries in Europe, North America, and Australia. Participants included 60,393 women ≥55 years attended by their physician during the previous 24 months. The sample was enriched so that two thirds were ≥65 years. Baseline surveys were mailed October 2006 to February 2008. Main outcome measures were self-perception of fracture risk in women with elevated risk vs women of the same age and frequency of risk factors for fragility fracture. RESULTS: In the overall study population, 19% (10,951/58,434) of women rated their risk of fracture as a little/much higher than that of women of the same age; 46% (27,138/58,434) said it was similar; 35% (20,345/58,434) believed it to be a little/much lower. Among women whose actual risk was increased based on the presence of any one of seven risk factors for fracture, the proportion who recognized their increased risk ranged from 19% for smokers to 39% for current users of glucocorticoid medication. Only 33% (4,185/12,612) of those with ≥2 risk factors perceived themselves as being at higher risk. Among women reporting a diagnosis of osteopenia or osteoporosis, only 25% and 43%, respectively, thought their risk was increased. CONCLUSION: In this international, observational study, most postmenopausal women with risk factors failed to appreciate their actual risk for fracture.

Fusion-fission experiments in Aphidius: evolutionary split without isolation in response to environmental bimodality.

Studying host-based divergence naturally maintained by a balance between selection and gene flow can provide valuable insights into genetic underpinnings of host adaptation and ecological speciation in parasites. Selection-gene flow balance is often postulated in sympatric host races, but direct experimental evidence is scarce. In this study, we present such evidence obtained in host races of Aphidius ervi, an important hymenopteran agent of biological control of aphids in agriculture, using a novel fusion-fission method of gene flow perturbation. In our study, between-race genetic divergence was obliterated by means of advanced hybridisation, followed by a multi-generation exposure of the resulting genetically uniform hybrid swarm to a two-host environment. This fusion-fission procedure was implemented under two contrasting regimes of between-host gene flow in two replicated experiments involving different racial pairs. Host-based genetic fission in response to environmental bimodality occurred in both experiments in as little as six generations of divergent adaptation despite continuous gene flow. We demonstrate that fission recovery of host-based divergence evolved faster and hybridisation-induced linkage disequilibrium decayed slower under restricted (6.7%) compared with unrestricted gene flow, directly pointing at a balance between gene flow and divergent selection. We also show, in four separate tests, that random drift had no or little role in the observed genetic split. Rates and patterns of fission divergence differed between racial pairs. Comparative linkage analysis of these differences is currently under way to test for the role of genomic architecture of adaptation in ecology-driven divergent evolution.

Squeezing protein shells: how continuum elastic models, molecular dynamics simulations, and experiments coalesce at the nanoscale.

The current rapid growth in the use of nanosized particles is fueled in part by our increased understanding of their physical properties and ability to manipulate them, which is essential for achieving optimal functionality. Here we report detailed quantitative measurements of the mechanical response of nanosized protein shells (viral capsids) to large-scale physical deformations and compare them with theoretical descriptions from continuum elastic modeling and molecular dynamics (MD). Specifically, we used nanoindentation by atomic force microscopy to investigate the complex elastic behavior of Hepatitis B virus capsids. These capsids are hollow, approximately 30 nm in diameter, and conform to icosahedral (5-3-2) symmetry. First we show that their indentation behavior, which is symmetry-axis-dependent, cannot be reproduced by a simple model based on Föppl-von Kármán thin-shell elasticity with the fivefold vertices acting as prestressed disclinations. However, we can properly describe the measured nonlinear elastic and orientation-dependent force response with a three-dimensional, topographically detailed, finite-element model. Next, we show that coarse-grained MD simulations also yield good agreement with our nanoindentation measurements, even without any fitting of force-field parameters in the MD model. This study demonstrates that the material properties of viral nanoparticles can be correctly described by both modeling approaches. At the same time, we show that even for large deformations, it suffices to approximate the mechanical behavior of nanosized viral shells with a continuum approach, and ignore specific molecular interactions. This experimental validation of continuum elastic theory provides an example of a situation in which rules of macroscopic physics can apply to nanoscale molecular assemblies.