Objective
Autoantibodies, such as anti–citrullinated protein antibodies (ACPAs), have been described as inducing bone loss in rheumatoid arthritis (RA), which can also be reflected by bone mineral ...density (BMD). We therefore examined the association between osteoporosis and autoantibodies in two independent RA cohorts.
Methods
Dual x‐ray absorptiometry (DXA) of the lumbar spine and left hip was performed in 408 Dutch patients with early RA during 5 years of follow‐up and in 198 Swedish patients with early RA during 10 years of follow‐up. The longitudinal effect of ACPAs and other autoantibodies on several BMD measures was assessed using generalized estimating equations.
Results
In the Dutch cohort, significantly lower BMD at baseline was observed in ACPA‐positive patients compared to ACPA‐negative patients, with an estimated marginal mean BMD in the left hip of 0.92 g/cm2 (95% confidence interval 95% CI 0.91–0.93) versus 0.95 g/cm2 (95% CI 0.93–0.97) (P = 0.01). In line with this, significantly lower Z scores at baseline were noted in the ACPA‐positive group compared to the ACPA‐negative group (estimated marginal mean Z score in the left hip of 0.18 95% CI 0.08–0.29 versus 0.48 95% CI 0.33–0.63) (P < 0.01). However, despite clear differences at baseline, ACPA positivity was not associated with greater decrease in absolute BMD or Z scores over time. Furthermore, there was no association between BMD and higher levels of ACPAs or other autoantibodies (rheumatoid factor and anti–carbamylated protein antibodies). In the Swedish cohort, ACPA‐positive patients tended to have a higher prevalence of osteopenia at baseline (P = 0.04), but again, ACPA positivity was not associated with an increased prevalence of osteopenia or osteoporosis over time.
Conclusion
The presence of ACPAs is associated with significantly lower BMD at baseline, but not with greater BMD loss over time in treated RA patients. These results suggest that ACPAs alone do not appear to contribute to bone loss after disease onset when disease activity is well‐managed.
Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect ...osteoporosis risk in the general population.
To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk.
Prospective, multicenter, collaborative study of individual-level data on 37,534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures.
Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures.
The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n = 25,052 number of participants with available data; 20-mg/cm2 lower BMD per Met667 allele copy; P = 3.3 x 10(-8)), as was the Val1330 allele (n = 24,812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 x 10(-9)). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P = 3.8 x 10(-5)) and 8 mg/cm2 (P = 5.0 x 10(-6)) for the Met667 and Val1330 alleles, respectively (n = 25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio OR, 1.26; 95% confidence interval CI, 1.08-1.47 for Met667 2001 fractures among 20 488 individuals and OR, 1.12; 95% CI, 1.01-1.24 for Val1330 1988 fractures among 20,096 individuals). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05-1.24 per allele 7876 fractures among 31,435 individuals)) and Val1330 (OR, 1.06; 95% CI, 1.01-1.12 per allele 7802 fractures among 31 199 individuals). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments.
Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance herein, unadjusted P < 10(-7) that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.
Summary
The International Osteoporosis Foundation (IOF) Capture the Fracture Campaign aims to support implementation of Fracture Liaison Services (FLS) throughout the world.
Introduction
FLS have ...been shown to close the ubiquitous secondary fracture prevention care gap, ensuring that fragility fracture sufferers receive appropriate assessment and intervention to reduce future fracture risk.
Methods
Capture the Fracture has developed internationally endorsed standards for best practice, will facilitate change at the national level to drive adoption of FLS and increase awareness of the challenges and opportunities presented by secondary fracture prevention to key stakeholders. The Best Practice Framework (BPF) sets an international benchmark for FLS, which defines essential and aspirational elements of service delivery.
Results
The BPF has been reviewed by leading experts from many countries and subject to beta-testing to ensure that it is internationally relevant and fit-for-purpose. The BPF will also serve as a measurement tool for IOF to award ‘Capture the Fracture Best Practice Recognition’ to celebrate successful FLS worldwide and drive service development in areas of unmet need. The Capture the Fracture website will provide a suite of resources related to FLS and secondary fracture prevention, which will be updated as new materials become available. A mentoring programme will enable those in the early stages of development of FLS to learn from colleagues elsewhere that have achieved Best Practice Recognition. A grant programme is in development to aid clinical systems which require financial assistance to establish FLS in their localities.
Conclusion
Nearly half a billion people will reach retirement age during the next 20 years. IOF has developed Capture the Fracture because this is the single most important thing that can be done to directly improve patient care, of both women and men, and reduce the spiralling fracture-related care costs worldwide.
Summary
We describe the collection of cohorts together with the analysis plan for an update of the fracture risk prediction tool FRAX with respect to current and novel risk factors. The resource ...comprises 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures.
Introduction
The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors.
Methods
A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible.
Results
Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of the cohort-specific beta coefficients for each risk factor, models comprising 10-year probability of hip and major osteoporotic fracture, with or without femoral neck bone mineral density, will be computed.
Conclusions
These assembled cohorts and described models will provide the framework for an updated FRAX tool enabling enhanced assessment of fracture risk (PROSPERO (CRD42021227266)).
Summary
The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were ...associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm.
Introduction
Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD).
Methods
The resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients.
Results
Falls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33–1.51) and men (HR 1.53, 95% CI 1.41–1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27–1.84) in men vs. HR 1.32 (95% CI 1.20–1.45) in women,
P
for interaction = 0.013). The HRs associated with previous falls decreased with age in women and with duration of follow-up in men and women for most fracture outcomes. There was no evidence of an interaction between falls and BMD for fracture risk. Subsequent risk for a major osteoporotic fracture increased with each additional previous fall in women and men.
Conclusions
A previous self-reported fall confers an increased risk of fracture that is largely independent of BMD. Previous falls should be considered as an additional risk factor in future iterations of FRAX to improve fracture risk prediction.
Estimating the contribution of demographic parameters to changes in population growth is essential for understanding why populations fluctuate. Integrated population models (IPMs) offer a possibility ...to estimate the contributions of additional demographic parameters, for which no data have been explicitly collected—typically immigration. Such parameters are often subsequently highlighted as important drivers of population growth. Yet, accuracy in estimating their temporal variation, and consequently their contribution to changes in population growth rate, has not been investigated.
To quantify the magnitude and cause of potential biases when estimating the contribution of immigration using IPMs, we simulated data (using northern wheatear Oenanthe oenanthe population estimates) from controlled scenarios to examine potential biases and how they depend on IPM parameterization, formulation of priors, the level of temporal variation in immigration and sample size. We also used empirical data on populations with known rates of immigration: Soay sheep Ovis aries and Mauritius kestrel Falco punctatus with zero immigration and grey wolf Canis lupus in Scandinavia with near‐zero immigration.
IPMs strongly overestimated the contribution of immigration to changes in population growth in scenarios when immigration was simulated with zero temporal variation (proportion of variance attributed to immigration = 63% for the more constrained formulation and real sample size) and in the wild populations, where the true number of immigrants was zero or near‐zero (kestrel 19.1%–98.2%, sheep 4.2%–36.1% and wolf 84.0%–99.2%). Although the estimation of the contribution of immigration in the simulation study became more accurate with increasing temporal variation and sample size, it was often not possible to distinguish between an accurate estimation from data with high temporal variation versus an overestimation from data with low temporal variation. Unrealistically, large sample sizes may be required to estimate the contribution of immigration well.
To minimize the risk of overestimating the contribution of immigration (or any additional parameter) in IPMs, we recommend to: (a) look for evidence of variation in immigration before investigating its contribution to population growth, (b) simulate and model data for comparison to the real data and (c) use explicit data on immigration when possible.
Résumé
Estimer la contribution des paramètres démographiques aux changements de croissance des populations est essentiel pour comprendre pourquoi les populations fluctuent. Les modèles de population intégrés (IPMs) offrent la possibilité d'estimer la contribution de paramètres démographiques additionnels, pour lesquels aucune donnée n'est explicitement collectée : typiquement l'immigration. De tels paramètres sont souvent mis en évidence comme étant des moteurs importants de la croissance des populations. Toutefois, la justesse de l'estimation de leur variation temporelle, et donc de leur contribution aux changements du taux de croissance, n'a pas été examinée.
Pour quantifier la magnitude et la cause de biais potentiels lors de l'estimation de la contribution de l'immigration avec des IPMs, nous avons simulé des données (en utilisant des estimations issues d'une population de traquet motteux Oenanthe oenanthe) afin d'examiner ces biais en fonction de la paramétrisation de l’IPM, la formulation des priors, le degré de variation temporelle de l'immigration et la taille d’échantillon. Nous avons également utilisé des données empiriques issues de populations aux taux d'immigration connus : le mouton de Soay Ovis aries et la crécerelle de Maurice Falco punctatus sans immigration et le loup gris Canis lupus en Scandinavie avec une immigration quasi‐nulle.
Les IPMs surestiment fortement la contribution de l'immigration aux changements de croissance des populations pour les scénarios où l'immigration était simulée sans variation temporelle (proportion de variance attribuée à l'immigration =63% pour la formulation la plus contrainte et la taille d’échantillon réelle) et pour les populations sauvages, où le vrai nombre d'immigrants était nul ou quasi‐nul (crécerelle 19.1%–98.2%, mouton 4.2%‐36.1%, loup 84.0%–99.2%). Même si l'estimation de la contribution de l'immigration s'améliore lorsque la variation temporelle ou la taille d’échantillon augmentent, il était généralement impossible de distinguer entre une estimation correcte issue de donnés avec haute variation temporelle versus une surestimation issue de donnés avec faible variation temporelle. Seules des tailles d’échantillon déraisonnablement élevées pourraient permettre d'estimer précisément la contribution de l'immigration.
Pour minimiser le risque de surestimer la contribution de l'immigration (ou autre paramètre additionnel) avec des IPMs, nous recommandons (i) de rechercher des preuves de variation de l'immigration avant d’étudier sa contribution à la croissance des populations, (ii) de simuler et modéliser des donnés pour comparer avec des données réelles et (iii) d'utiliser des donnés explicites sur l'immigrations lorsque cela est possible.
Why and how new migration routes emerge remain fundamental questions in ecology, particularly in the context of current global changes. In its early stages, when few individuals are involved, the ...evolution of new migration routes can be easily confused with vagrancy, i.e. the occurrence of individuals outside their regular breeding, non-breeding or migratory distribution ranges. Yet, vagrancy can in theory generate new migration routes if vagrants survive, return to their breeding grounds and transfer their new migration route to their offspring, thus increasing a new migratory phenotype in the population. Here, we review the conceptual framework and empirical challenges of distinguishing regular migration from vagrancy in small obligate migratory passerines and explain how this can inform our understanding of migration evolution. For this purpose, we use the Yellow-browed Warbler (Phylloscopus inornatus) as a case study. This Siberian species normally winters in southern Asia and its recent increase in occurrence in Western Europe has become a prominent evolutionary puzzle. We first review and discuss available evidence suggesting that the species is still mostly a vagrant in Western Europe but might be establishing a new migration route initiated by vagrants. We then list possible empirical approaches to check if some individuals really undertake regular migratory movements between Western Europe and Siberia, which would make this species an ideal model for studying the links between vagrancy and the emergence of new migratory routes.
Summary
A large international meta-analysis using primary data from 64 cohorts has quantified the increased risk of fracture associated with a previous history of fracture for future use in FRAX.
...Introduction
The aim of this study was to quantify the fracture risk associated with a prior fracture on an international basis and to explore the relationship of this risk with age, sex, time since baseline and bone mineral density (BMD).
Methods
We studied 665,971 men and 1,438,535 women from 64 cohorts in 32 countries followed for a total of 19.5 million person-years. The effect of a prior history of fracture on the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture, and hip fracture alone was examined using an extended Poisson model in each cohort. Covariates examined were age, sex, BMD, and duration of follow-up. The results of the different studies were merged by using the weighted
β
-coefficients.
Results
A previous fracture history, compared with individuals without a prior fracture, was associated with a significantly increased risk of any clinical fracture (hazard ratio, HR = 1.88; 95% CI = 1.72–2.07). The risk ratio was similar for the outcome of osteoporotic fracture (HR = 1.87; 95% CI = 1.69–2.07), major osteoporotic fracture (HR = 1.83; 95% CI = 1.63–2.06), or for hip fracture (HR = 1.82; 95% CI = 1.62–2.06). There was no significant difference in risk ratio between men and women. Subsequent fracture risk was marginally downward adjusted when account was taken of BMD. Low BMD explained a minority of the risk for any clinical fracture (14%), osteoporotic fracture (17%), and for hip fracture (33%). The risk ratio for all fracture outcomes related to prior fracture decreased significantly with adjustment for age and time since baseline examination.
Conclusion
A previous history of fracture confers an increased risk of fracture of substantial importance beyond that explained by BMD. The effect is similar in men and women. Its quantitation on an international basis permits the more accurate use of this risk factor in case finding strategies.
Summary
Romosozumab is a novel bone-building drug that reduces fracture risk. This health economic analysis indicates that sequential romosozumab-to-alendronate can be a cost-effective treatment ...option for postmenopausal women with severe osteoporosis at high risk of fracture.
Purpose
To estimate the cost-effectiveness of sequential treatment with romosozumab followed by alendronate (“romosozumab-to-alendronate”) compared with alendronate alone in patients with severe osteoporosis at high risk of fracture in Sweden.
Methods
A microsimulation model with a Markov structure was used to simulate fractures, costs, and quality-adjusted life years (QALYs), for women treated with romosozumab-to-alendronate or alendronate alone. Patients aged 74 years with a recent major osteoporotic fracture (MOF) were followed from the start of treatment until the age of 100 years or death. Treatment with romosozumab for 12 months was followed by alendronate for up to 48 months or alendronate alone with a maximum treatment duration of 60 months. The analysis had a societal perspective. Efficacy of romosozumab and alendronate were derived from phase III randomized controlled trials. Resource use and unit costs were collected from the literature. Cost-effectiveness was estimated using incremental cost-effectiveness ratio (ICER) with QALYs as effectiveness measures.
Results
The base case analysis showed that sequential romosozumab-to-alendronate treatment was associated with 0.089 additional QALYs at an additional cost of €3002 compared to alendronate alone, resulting in an ICER of €33,732. At a Swedish reference willingness-to-pay per QALY of €60,000, romosozumab-to-alendronate had a 97.9% probability of being cost-effective against alendronate alone. The results were most sensitive to time horizon, persistence assumptions, patient age, and treatment efficacy.
Conclusion
The results of this study indicate that sequential romosozumab-to-alendronate can be a cost-effective treatment option for postmenopausal women with severe osteoporosis at high risk of fracture.
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