Teresa Monjardino

Upregulation of Inflammatory Genes and Downregulation of Sclerostin Gene Expression Are Key Elements in the Early Phase of Fragility Fracture Healing

Background Fracture healing is orchestrated by a specific set of events that culminates in the repair of bone and reachievement of its biomechanical properties. The aim of our work was to study the sequence of gene expression events involved in inflammation and bone remodeling occurring in the early phases of callus formation in osteoporotic patients. Methodology/Principal Findings Fifty-six patients submitted to hip replacement surgery after a low-energy hip fracture were enrolled in this study. The patients were grouped according to the time interval between fracture and surgery: bone collected within 3 days after fracture (n = 13); between the 4th and 7th day (n = 33); and after one week from the fracture (n = 10). Inflammation- and bone metabolism-related genes were assessed at the fracture site. The expression of pro-inflammatory cytokines was increased in the first days after fracture. The genes responsible for bone formation and resorption were upregulated one week after fracture. The increase in RANKL expression occurred just before that, between the 4th–7th days after fracture. Sclerostin expression diminished during the first days after fracture. Conclusions The expression of inflammation-related genes, especially IL-6, is highest at the very first days after fracture but from day 4 onwards there is a shift towards bone remodeling genes, suggesting that the inflammatory phase triggers bone healing. We propose that an initial inflammatory stimulus and a decrease in sclerostin-related effects are the key components in fracture healing. In osteoporotic patients, cellular machinery seems to adequately react to the inflammatory stimulus, therefore local promotion of these events might constitute a promising medical intervention to accelerate fracture healing.

Associations between a priori -defined dietary patterns and longitudinal changes in bone mineral density in adolescents

OBJECTIVE To quantify short- and long-term associations between dietary patterns defined a priori and bone mineral density (BMD) during adolescence. DESIGN Dietary patterns were defined at 13 years old using a Mediterranean diet (MD) quality index, the Dietary Approaches to Stop Hypertension (DASH) diet index and the Oslo Health Study (OHS) dietary index. Linear regression coefficients were used to estimate associations between dietary patterns and forearm BMD at 13 and 17 years, measured by dual-energy X-ray absorptiometry. SETTING Public and private schools of Porto, Portugal. SUBJECTS The EPITeen cohort comprising 1180 adolescents born in 1990, recruited at schools during the 2003/2004 school year and re-evaluated in 2007/2008. RESULTS In girls, at 13 years, mean BMD (g/cm2) in the first and third tertiles was 0·369 and 0·368 for the MD pattern, 0·368 and 0·369 for the DASH diet, and 0·370 and 0·363 for the OHS index. In boys, mean BMD (g/cm2) in the first and third tertiles was 0·338 and 0·347 for the MD pattern, 0·342 and 0·346 for the DASH diet, and 0·344 and 0·342 for the OHS index. None of these differences were significant. Mean BMD at 17 years and prospective variation were also not significantly different between tertiles of adherence to each score. However, a trend of increased BMD at 13 years with greater adherence to the MD pattern was observed in boys (adjusted coefficient = 0·248; 95% CI 0·052, 0·444). CONCLUSIONS The selected dietary patterns may not capture truly important dietary differences in determining BMD or diet may not be, beyond nutrient adequacy, a limiting determinant of BMD.

Patterns and Consequences of Multimorbidity in the General Population: There is No Chronic Disease Management Without Rheumatic Disease Management

To identify empirical model‐based patterns of multimorbidity from chronic noncommunicable diseases in the general population, with a focus on the contribution of rheumatic and musculoskeletal diseases (RMDs), and to quantify their association with adverse health outcomes.

Low‐grade systemic inflammation and suboptimal bone mineral density throughout adolescence: a prospective study in girls

We aimed at quantifying the associations between high‐sensitivity C‐reactive protein (hs‐CRP) and forearm bone mineral density (BMD) throughout adolescence in overweight and normal‐weight girls.

Quantitative modelling of hip fracture trends in 14 European countries: Testing variations of a shared reversal over time

Qualitative similarities between hip fracture trends in different countries suggests variations of the same epidemic. We tested a single statistical shape to describe time trends in Europe, while allowing for country-level variability. Using data from 14 countries, we modelled incidence rates over time using linear mixed-effects models, including the fixed effects of calendar year and age. Random effects were tested to quantify country-level variability in background rates, timing of trend reversal and tempo of reversal. Mixture models were applied to identify clusters of countries defined by common behavioural features. A quadratic function of time, with random effects for background rates and timing of trend reversal, adjusted well to the observed data. Predicted trend reversal occurred on average in 1999 in women (peak incidence about 600 per 100 000) and 2000 in men (about 300 per 100 000). Mixture modelling of country-level effects suggested three clusters for women and two for men. In both sexes, Scandinavia showed higher rates but earlier trend reversals, whereas later trend reversals but lower peak incidences were found in Southern Europe and most of Central Europe. Our finding of a similar overall reversal pattern suggests that different countries show variations of a shared hip fracture epidemic.

Do bone mineral content and density determine fracture in children? A possible threshold for physical activity

BackgroundRelations between bone parameters, physical exertion, and childhood fractures are complex. We aimed to estimate the associations between fracture history and bone mineral content (BMC) and areal bone mineral density (aBMD) at 7 years of age, by levels of physical activity, as a proxy for trauma frequency.MethodsWe used data collected from 2,261 children of the Generation XXI birth cohort, assembled in 2005/6 in Porto, Portugal. At the age of 7 years (2012/4), fracture history, time spent per week in active play, and sports practice were reported by parents. Subtotal and lumbar spine (LS) BMC and aBMD were measured using whole-body dual-energy X-ray absorptiometry.ResultsBoys and girls in the highest categories of time spent in sports practice or active play generally had higher BMC and aBMD. Among girls, BMC and aBMD were protective of fracture only in the highest quarter of active play (>660 min/week)—odds ratios (OR; 95% confidence interval (95% CI)) for subtotal BMC=0.27 (0.11–0.67), subtotal aBMD=0.18 (0.06–0.49), and LS aBMD=0.41 (0.22–0.75). For boys in the highest quarter of sports practice (>240 min/week), subtotal and LS BMC were protective of fracture—OR=0.39 (0.16–0.98) and 0.51 (0.27–0.96), respectively.ConclusionIn prepubertal children, BMC and aBMD predicted fracture history only in the highest levels of physical activity.

The population impact of rheumatic and musculoskeletal diseases in relation to other non-communicable disorders: comparing two estimation approaches

The aim of this study was to quantify the population impact of rheumatic and musculoskeletal diseases (RMDs) with other non-communicable diseases (NCDs), using two complementary strategies: standard multivariate models based on global burden of disease (GBD)-defined groups vs. empirical mutually exclusive patterns of NCDs. We used cross-sectional data from the Portuguese Fourth National Health Survey (n = 23,752). Six GBD-defined groups were included: RMDs, chronic obstructive pulmonary disease or asthma, cancer, depression, diabetes or renal failure, and stroke or myocardial infarction. The empirical approach comprised the patterns “low disease probability”, “cardiometabolic conditions”, “respiratory conditions” and “RMDs and depression”. As recommended by the outcome measures in rheumatology (OMERACT) initiative, health outcomes included life impact, pathophysiological manifestations, and resource use indicators. Population attributable fractions (PAF) were computed for each outcome and bootstrap confidence intervals (95% CI) were estimated. Among GBD-defined groups, RMDs had the highest impact across all the adverse health outcomes, from frequent healthcare utilization (PAF 7.8%, 95% CI 6.2–9.3) to negative self-rated health (PAF 18.1%, 95% CI 15.4–20.6). In the empirical approach, patterns “cardiometabolic conditions” and “RMDs and depression” had similar PAF estimates across all adverse health outcomes, but “RMDs and depression” showed significantly higher impact on chronic pain (PAF 8.9%, 95% CI 7.6–10.3) than the remaining multimorbidity patterns. RMDs revealed the greatest population impact across all adverse health outcomes tested, using both approaches. Empirical patterns are particularly interesting to evaluate the impact of RMDs in the context of their co-occurrence with other NCDs.

Weight Trajectories from Birth and Bone Mineralization at 7 Years of Age

Objective To assess whether different trajectories of weight gain since birth influence bone mineral content (BMC) and areal bone mineral density (aBMD) at 7 years of age. Study design We studied a subsample of 1889 children from the Generation XXI birth cohort who underwent whole‐body dual‐energy radiograph absorptiometry. Weight trajectories identified through normal mixture modeling for model‐based clustering and labeled “normal weight gain,” “weight gain during infancy,” “weight gain during childhood,” and “persistent weight gain” were used. Differences in subtotal BMC, aBMD, and size‐corrected BMC (scBMC) at age 7 years according to weight trajectories were estimated through analysis of covariance. Results Compared with the “normal weight gain” trajectory, children in the remaining trajectories had significantly greater BMC, aBMD, and scBMC at age 7 years, with the strongest associations for “persistent weight gain” (girls [BMC: 674.0 vs 559.8 g, aBMD: 0.677 vs 0.588 g/cm2, scBMC: 640.7 vs 577.4 g], boys [BMC: 689.4 vs 580.8 g, aBMD: 0.682 vs 0.611 g/cm2, scBMC: 633.0 vs 595.6 g]). After adjustment for current weight, and alternatively for fat and lean mass, children with a “weight gain during childhood” trajectory had greater BMC and aBMD than those with a “normal weight gain” trajectory, although significant differences were restricted to girls (BMC: 601.4 vs 589.2 g, aBMD: 0.618 vs 0.609 g/cm2). Conclusion Overall, children following a trajectory of persistent weight gain since birth had clearly increased bone mass at 7 years, but weight gain seemed slightly more beneficial when it occurred later rather than on a normal trajectory during the first 7 years of life.

Cohort study shows that peripheral dual‐energy X‐ray absorptiometry is of limited epidemiologic use in prepubertal children

Peripheral methods are increasingly used to assess bone health, despite little evidence on their predictive ability. We aimed to evaluate the usefulness of forearm dual‐energy X‐ray absorptiometry in prepubertal children, by estimating the agreement between peripheral and central measures and the ability to predict fracture history.

Upregulation of inflammatory genes and downregulation of sclerostin are key elements for fracture healing

Methods Fifty-six patients submitted to hip replacement surgery after a low-energy hip fracture were enrolled in this study. The patients were stratified according to the time interval between fracture and surgery: bone collected within 3 days after fracture (n=13); between the 4 and 7 day (n=33); and after one week from the fracture (n=10). Inflammationand bone metabolism-related genes were assessed in trabecular bone.