Comorbidities only account for a small proportion of excess mortality after fracture: A record linkage study of individual fracture types

Background: Non-hip non-vertebral fractures (NHNV) constitute the majority of osteoporotic fractures but few studies have examined the association between these fractures, co-morbidity and mortality. Objective: To examine the relationship between individual non-hip non-vertebral fractures, co-morbidities and mortality. Methods: Prospective population-based cohort of 267,043 subjects (45 and Up Study, Australia) had baseline questionnaires linked to hospital administrative and all-cause mortality data from 2006 - 2013. Associations between fracture and mortality examined using multivariate, time dependent Cox models, adjusted for age, prior fracture, body mass index, smoking and co-morbidities (cardiovascular disease, diabetes, stroke, thrombosis and cancer) and survival function curves. Population attributable fraction calculated for each level of risk exposure. Results: During 1,490,651 person-years, women and men experienced 7,571 and 4,571 fractures and 7,064 deaths and 11,078 deaths, respectively. In addition to hip and vertebral fractures, pelvis, humerus, clavicle, rib, proximal tibia/fibula, elbow and distal forearm fractures in both sexes, and ankle fractures in men, were associated with increased multivariable adjusted mortality hazard ratios ranging from 1.3 to 3.4. Co-morbidity independently added to mortality such that a woman with a humeral fracture and one co-morbidity had a similarly reduced 5 year survival to that of a woman with a hip fracture and no co-morbidities. Population mortality attributable to any fracture without co-morbidity was 9.2% in women and 5.3% in men. Conclusion: All proximal non-hip, non-vertebral fractures in women and men were associated with increased mortality risk. Co-existent co-morbidities independently further increased mortality. Population attributable risk for mortality for fracture was similar to cardiovascular disease and diabetes, highlighting their importance and potential benefit for early intervention and treatment

Nonstandard lumbar region in predicting fracture risk

Background: Femoral neck BMD is the most commonly used skeletal site to estimate fracture risk. The role of lumbar spine BMD in fracture risk prediction is less clear due to osteophytes that spuriously increase LS BMD, particularly at lower levels. The aim of this study was to compare fracture predictive ability of upper L1-L2 BMD compared to standard L2-L4 BMD and assess whether the addition of either lumbar spine site could improve fracture prediction over FN BMD. Methodology: A prospective cohort of 3016 women and men 60+ years from the Dubbo Osteoporosis Epidemiology Study followed for occurrence of minimal trauma fractures from 1989 to 2014. DXA was used to measure bone mineral density at f L1-L2, L2-L4 and FN at baseline. Fracture risks were estimated using Cox proportional hazards models separately for each site. Predictive performances were compared using ROC curve analyses Results:There were 565 women and 179 men with a minimal trauma fracture during a mean of 11±7 years. L1-L2 BMD T-score was significantly lower than L2-L4 T-score in both genders (p Conclusion: In an elderly population, L1-L2 is as good as but not better than L2-L4 site in predicting fracture risk. The addition of LS BMD to FN BMD provided a modest additional benefit in overall fracture risk. Further studies in individuals with spinal degenerative disease are needed

Reduced mortality and subsequent fracture risk associated with oral bisphosphonate recommendation in a fracture liaison service setting: A prospective cohort study

Objective: Osteoporotic fragility fractures, that are common in men and women, signal increased risk of future fractures and of premature mortality. Less than one-third of postmenopausal women and fewer men are prescribed active treatments to reduce fracture risk. Therefore, in this study the association of oral bisphosphonate recommendation with subsequent fracture and mortality over eight years in a fracture liaison service setting was analysed. Materials and methods: In this prospective cohort study, 5011 men and women aged \u3e50 years, who sustained a clinical fracture, accepted the invitation to attend the fracture liaison service of the West Glasgow health service between 1999 and 2007. These patients were fully assessed and all were recommended calcium and vitamin D. Based on pre-defined fracture risk criteria, 2534 (50.7%) patients were additionally also recommended oral bisphosphonates. Mortality and subsequent fracture risk were the pre-defined outcomes analysed using Cox proportional hazard models. Results: Those recommended bisphosphonates were more often female (82.9 vs. 72.4%), were older (73.4 vs. 64.4 years), had lower bone mineral density T-score (-3.1 vs. -1.5) and more had sustained hip fractures (21.7 vs. 6.2%; p \u3c 0.001). After adjustments, patients recommended bisphosphonates had lower subsequent fracture risk (Hazard Ratio (HR): 0.60; 95% confidence interval (CI): 0.49±0.73) and lower mortality risk (HR: 0.79, 95%CI: 0.64±0.97). Conclusion: Of the patients, who are fully assessed after a fracture at the fracture liaison service, those with higher fracture risk and a recommendation for bisphosphonates had worse baseline characteristics. However, after adjusting for these differences, those recommended bisphosphonate treatment had a substantially lower risk for subsequent fragility fracture and lower risk for mortality. These community-based data indicate the adverse public health outcomes and mortality impacts of the current low treatment levels post fracture could be improved by bisphosphonate recommendation for both subsequent fracture and mortality

The Challenges and Opportunities of Pharmacoepidemiology in Bone Diseases

Altres ajuts: This work was supported by the National Health Medical Research Council Australia (NHMRC project ID; DA 1114676, DB 1073430, and JRC 1008219). This work was partially supported by the NIHR Biomedical Research Centre, Oxford. DPA is funded by a National Institute for Health Research Clinician Scientist award (CS-2013-13-012). This article presents independent research funded by the National Institute for Health Research (NIHR). Other funding bodies were the Bupa Health Foundation (formerly MBF Foundation) and the Mrs Gibson and Ernst Heine Family Foundation. The views expressed are those of the authors and not necessarily those of the NHMRC and the NIHR.Pharmacoepidemiology is used extensively in osteoporosis research and involves the study of the use and effects of drugs in large numbers of people. Randomized controlled trials are considered the gold standard in assessing treatment efficacy and safety. However, their results can have limited external validity when applied to day-to-day patients. Pharmacoepidemiological studies aim to assess the effect/s of treatments in actual practice conditions, but they are limited by the quality, completeness, and inherent bias due to confounding. Sources of information include prospectively collected (primary) as well as readily available routinely collected (secondary) (eg, electronic medical records, administrative/claims databases) data. Although the former enable the collection of ad hoc measurements, the latter provide a unique opportunity for the study of large representative populations and for the assessment of rare events at relatively low cost. Observational cohort and case-control studies, the most commonly implemented study designs in pharmacoepidemiology, each have their strengths and limitations. However, the choice of the study design depends on the research question that needs to be answered. Despite the many advantages of observational studies, they also have limitations. First, missing data is a common issue in routine data, frequently dealt with using multiple imputation. Second, confounding by indication arises because of the lack of randomization; multivariable regression and more specific techniques such as propensity scores (adjustment, matching, stratification, trimming, or weighting) are used to minimize such biases. In addition, immortal time bias (time period during which a subject is artefactually event-free by study design) and time-varying confounding (patient characteristics changing over time) are other types of biases usually accounted for using time-dependent modeling. Finally, residual "uncontrolled" confounding is difficult to assess, and hence to account for it, sensitivity analyses and specific methods (eg, instrumental variables) should be considered. © 2018 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research

Epidemiological transition to mortality and refracture following an initial fracture

This study sought to redefine the concept of fracture risk that includes refracture and mortality, and to transform the risk into "skeletal age". We analysed data obtained from 3521 women and men aged 60 years and older, whose fracture incidence, mortality, and bone mineral density (BMD) have been monitored since 1989. During the 20-year follow-up period, among 632 women and 184 men with a first incident fracture, the risk of sustaining a second fracture was higher in women (36%) than in men (22%), but mortality risk was higher in men (41%) than in women (25%). The increased risk of mortality was not only present with an initial fracture, but was accelerated with refractures. Key predictors of post-fracture mortality were male gender (hazard ratio [HR] 2.4; 95% CI, 1.79–3.21), advancing age (HR 1.67; 1.53–1.83), and lower femoral neck BMD (HR 1.16; 1.01–1.33). A 70-year-old man with a fracture is predicted to have a skeletal age of 75. These results were incorporated into a prediction model to aid patient-doctor discussion about fracture vulnerability and treatment decisions

External validation of the Garvan nomograms for predicting absolute fracture risk: The Tromso study

Background: Absolute risk estimation is a preferred approach for assessing fracture risk and treatment decision making. This study aimed to evaluate and validate the predictive performance of the Garvan Fracture Risk Calculator in a Norwegian cohort. Methods: The analysis included 1637 women and 1355 aged 60+ years from the Tromsø study. All incident fragility fractures between 2001 and 2009 were registered. The predicted probabilities of non-vertebral osteoporotic and hip fractures were determined using models with and without BMD. The discrimination and calibration of the models were assessed.Reclassification analysis was used to compare the models performance. Results: The incidence of osteoporotic and hip fracture was 31.5 and 8.6 per 1000 population in women, respectively; in men the corresponding incidence was 12.2 and 5.1. The predicted 5-year and 10-year probability of fractures was consistently higher in the fracture group than the non-fracture group for all models. The 10-year predicted probabilities of hip fracture in those with fracture was 2.8 (women) to 3.1 times (men) higher than those without fracture. There was a close agreement between predicted and observed risk in both sexes and up to the fifth quintile. Among those in the highest quintile of risk, the models over-estimated the risk of fracture. Models with BMD performed better than models with body weight in correct classification of risk in individuals with and without fracture. The overall net decrease in reclassification of the model with weight compared to the model with BMD was 10.6% (p = 0.008) in women and 17.2% (p = 0.001) in men for osteoporotic fractures, and 13.3% (p = 0.07) in women and 17.5% (p = 0.09) in men for hip fracture. Conclusions: The Garvan Fracture Risk Calculator is valid and clinically useful in identifying individuals at high risk of fracture. The models with BMD performed better than those with body weight in fracture risk prediction

A Risk Assessment Tool for Predicting Fragility Fractures and Mortality in the Elderly

Existing fracture risk assessment tools are not designed to predict fracture-associated consequences, possibly contributing to the current undermanagement of fragility fractures worldwide. We aimed to develop a risk assessment tool for predicting the conceptual risk of fragility fractures and its consequences. The study involved 8965 people aged >= 60 years from the Dubbo Osteoporosis Epidemiology Study and the Canadian Multicentre Osteoporosis Study. Incident fracture was identified from X-ray reports and questionnaires, and death was ascertained though contact with a family member or obituary review. We used a multistate model to quantify the effects of the predictors on the transition risks to an initial and subsequent incident fracture and mortality, accounting for their complex interrelationships, confounding effects, and death as a competing risk. There were 2364 initial fractures, 755 subsequent fractures, and 3300 deaths during a median follow-up of 13 years (interquartile range [IQR] 7-15). The prediction model included sex, age, bone mineral density, history of falls within 12 previous months, prior fracture after the age of 50 years, cardiovascular diseases, diabetes mellitus, chronic pulmonary diseases, hypertension, and cancer. The model accurately predicted fragility fractures up to 11 years of follow-up and post-fracture mortality up to 9 years, ranging from 7 years after hip fractures to 15 years after non-hip fractures. For example, a 70-year-old woman with aT-score of -1.5 and without other risk factors would have 10% chance of sustaining a fracture and an 8% risk of dying in 5 years. However, after an initial fracture, her risk of sustaining another fracture or dying doubles to 33%, ranging from 26% after a distal to 42% post hip fracture. A robust statistical technique was used to develop a prediction model for individualization of progression to fracture and its consequences, facilitating informed decision making about risk and thus treatment for individuals with different risk profiles. (c) 2020 American Society for Bone and Mineral Research

Reduced bone loss is associated with reduced mortality risk in subjects exposed to nitrogen bisphosphonates: A mediation analysis

Bisphosphonates, potent anti-resorptive agents, have been found to be associated with mortality reduction. Accelerated bone loss is, in itself, an independent predictor of mortality risk, but the relationship between bisphosphonates, bone loss, and mortality is unknown. This study aimed to determine whether the association between bisphosphonates and mortality is mediated by a reduction in the rate of bone loss. Participants from the population‐based Canadian Multicentre Osteoporosis Study were followed prospectively between1996 and 2011. Comorbidities and lifestyle factors were collected at baseline and bone mineral density (BMD) at baseline and at years 3 (for those aged 40 to 60 years), 5, and 10. Rate of bone loss was calculated using linear regression. Information on medication use was obtained yearly. Bisphosphonate users grouped into nitrogen bisphosphonates (nBP; alendronate or risedronate) and etidronate and non‐users (NoRx) were matched by propensity score, including all baseline factors as well as time of treatment. Cox’s proportional hazards models, unadjusted and adjusted for annual rate of bone loss, were used to determine the association between nBP and etidronate versus NoRx. For the treatment groups with significant mortality risk reduction, the percent of mortality reduction mediated by a reduction in the rate of bone loss was estimated using a causal mediation analysis. There were 271 pairs of nBP and matched NoRx and 327 pairs of etidronate and matched NoRx. nBP but not etidronate use was associated with significant mortality risk reduction (hazard ratios [HR]=0.61 [95% confidenceinterval0.39–0.96]and1.35[95%CI0.86–2.11] for nBP and etidronate, respectively). Rapid bone loss was associated with more than2‐fold increased mortality risk compared with no loss. Mediation analysis indicated that39% (95%CI7%–84%) of the nBP association with mortality was related to a reduction in the rate of bone loss. This finding provides an insight into the mechanism of the relationship between nBP and survival benefit in osteoporotic patients

Risk and predictors of poor outcome following osteoporotic fractures

Osteoporotic fractures represent a major public health problem because of their increased morbidity, mortality and cost to the community. This thesis aimed to examine the long-term risk and predictors of poor outcomes following fracture including refracture and mortality as well as the effect of osteoporosis medication on mortality risk. All minimal trauma fractures and mortality data were collected from 2245 women and 1760 men aged 60 + years participating in Dubbo Osteoporosis Epidemiology Study between April 1989 and May 2007.Initial fracture risk increased exponentially with age and was higher in women. Following the initial fracture, re-fracture risk was increased by 1.6-2.4-fold for women and 2.8-4.3-fold for men, resulting in an overall re-fracture risk that was comparable for women and men and worse than that of an initial fracture risk of women 10 years older. Re-fracture risk was highest for those with osteoporosis, but still increased for those with non-osteoporotic BMD.Mortality risk was increased by 1.7- 3.6-fold following hip, vertebral and major fractures for all ages and minor fractures in the elderly. Low BMD, having smoked and increased sway were independent mortality predictors in women, and physical inactivity and fewer falls in men.Mortality and re-fracture risks were highest in the first 5 years post-fracture. During this interval 26% of women and 41% of men died and 37% of women and 24 % of men re-fractured. Both re-fracture and mortality risks subsequently declined. However, following re-fracture, mortality risk again increased 2-fold.Individuals who received bisphosphonate had better survival than those not treated. In multivariable analysis this reduction remained significant in women with a similar but non-significant effect size in men likely due to smaller numbers. Hormone therapy and calcium ±vitamin D supplements were not associated with survival benefit.These data have shown a high cumulative risk (>80%) of multiple adverse events following an osteoporotic fracture. Those who survive the initial fracture have increased re-fracture risk which further increases mortality risk. Bisphosphonate may improve survival in women and perhaps men. Thus, this thesis give an insight into the overall burden of post-fracture events and provided evidence that osteoporosis treatment may help improve survival