Estimating the economic burden of osteoporotic fractures in a multinational study: a real-world data perspective.

Fracture-related costs vary by country. A standardized methodology and presentations were proposed to fairly assess the economic burden of osteoporotic fracture. Results indicated substantial costs of osteoporotic fractures for pharmacy, hospitalization, emergency care, and outpatient visits in women aged ≥ 50 years in Australia, Germany, South Korea, Spain, and the USA. PURPOSE: The objective of this multinational, retrospective matched cohort study was to use a standardized methodology across different healthcare systems to estimate the burden of osteoporotic fracture (OF) in women aged ≥ 50 years in Australia, Germany, South Korea, Spain, and the USA. METHODS: Within each country, healthcare resource utilization and direct costs of care were compared between patients with newly identified OF and a propensity score-matched cohort without OF during follow-up periods of up to 5 years. RESULTS: Across all five countries, the OF cohort had significantly higher rates and length of inpatient admissions compared with the non-OF cohort. In each country, the adjusted total costs of care ratio between OF and non-OF cohorts were significant. The adjusted cost ratios for pharmacy, inpatient care, emergency care, and outpatient visits were similarly higher in the OF cohort across countries. CONCLUSION: The current study demonstrates the substantial economic burden of OF across different countries when compared with matched non-OF patients. The findings would assist stakeholders and policymakers in developing appropriate health policies.

Persistence and compliance with osteoporosis therapies among postmenopausal women in the UK Clinical Practice Research Datalink.

Gaining full benefits from osteoporosis medications requires long-term treatment. Investigating the real-world persistence of women receiving osteoporosis medications in the UK, we found that most patients stop treatment within a year. To prevent osteoporotic fragility fractures, long-term treatment persistence must be improved. INTRODUCTION: Persistence with osteoporosis therapies has historically been poor. To treat this chronic and progressive disease, it is essential that patients receive the full benefit of these medications. We estimated persistence and compliance with osteoporosis therapies in a large sample of postmenopausal women in the UK. METHODS: Data were obtained from the Clinical Practice Research Datalink for all women aged 50 years and over or women with early menopause, who received at least one prescription in primary care for any licensed osteoporosis therapy between January 1, 2010 and December 31, 2015. Persistence and compliance at 24 months (primary objective) and at 5 years (exploratory objective) were estimated in three patient cohorts: "All Patients," "Naïve Patients," and "Drug-Specific." RESULTS: The All Patients cohort included 72,256 women. Persistence with any therapy was 56.1%, 43.6%, 36.4%, and 31.0% at 6, 12, 18, and 24 months, respectively, and 23.2% and 13.1% at 3 years and 5 years, respectively. Patients were generally more persistent and compliant if evaluated from their first exposure to osteoporosis therapy (Naïve Patients cohort). In the drug-specific analysis, 64% of patients receiving denosumab (administered subcutaneously every 6 months) were persistent at 24 months compared with 28% and 23% of those taking oral bisphosphonates and intravenous bisphosphonates, respectively. CONCLUSIONS: Only about one in three patients who received osteoporosis therapy continued to be on treatment after 2 years. There is a need to improve persistence with osteoporosis therapy, especially for high-risk patients.

Predictive ability of heel quantitative ultrasound for incident fractures: an individual-level meta-analysis.

UNLABELLED: The relationship between bone quantitative ultrasound (QUS) and fracture risk was estimated in an individual level data meta-analysis of 9 prospective studies of 46,124 individuals and 3018 incident fractures. Low QUS is associated with an increase in fracture risk, including hip fracture. The association with osteoporotic fracture decreases with time. INTRODUCTION: The aim of this meta-analysis was to investigate the association between parameters of QUS and risk of fracture. METHODS: In an individual-level analysis, we studied participants in nine prospective cohorts from Asia, Europe and North America. Heel broadband ultrasonic attenuation (BUA dB/MHz) and speed of sound (SOS m/s) were measured at baseline. Fractures during follow-up were collected by self-report and in some cohorts confirmed by radiography. An extension of Poisson regression was used to examine the gradient of risk (GR, hazard ratio per 1 SD decrease) between QUS and fracture risk adjusted for age and time since baseline in each cohort. Interactions between QUS and age and time since baseline were explored. RESULTS: Baseline measurements were available in 46,124 men and women, mean age 70 years (range 20-100). Three thousand and eighteen osteoporotic fractures (787 hip fractures) occurred during follow-up of 214,000 person-years. The summary GR for osteoporotic fracture was similar for both BUA (1.45, 95 % confidence intervals (CI) 1.40-1.51) and SOS (1.42, 95 % CI 1.36-1.47). For hip fracture, the respective GRs were 1.69 (95 % CI, 1.56-1.82) and 1.60 (95 % CI, 1.48-1.72). However, the GR was significantly higher for both fracture outcomes at lower baseline BUA and SOS (p < 0.001). The predictive value of QUS was the same for men and women and for all ages (p > 0.20), but the predictive value of both BUA and SOS for osteoporotic fracture decreased with time (p = 0.018 and p = 0.010, respectively). For example, the GR of BUA for osteoporotic fracture, adjusted for age, was 1.51 (95 % CI 1.42-1.61) at 1 year after baseline, but at 5 years, it was 1.36 (95 % CI 1.27-1.46). CONCLUSIONS: Our results confirm that quantitative ultrasound is an independent predictor of fracture for men and women particularly at low QUS values.

A higher alkaline dietary load is associated with greater indexes of skeletal muscle mass in women.

UNLABELLED: Conservation of muscle mass is important for fall and fracture prevention but further understanding of the causes of age-related muscle loss is required. This study found a more alkaline diet was positively associated with muscle mass in women suggesting a role for dietary acid-base load in muscle loss. INTRODUCTION: Conservation of skeletal muscle is important for preventing falls and fractures but age-related loss of muscle mass occurs even in healthy individuals. However, the mild metabolic acidosis associated with an acidogenic dietary acid-base load could influence loss of muscle mass. METHODS: We investigated the association between fat-free mass (FFM), percentage FFM (FFM%) and fat-free mass index (FFMI, weight/height²), measured using dual-energy X-ray absorptiometry in 2,689 women aged 18-79 years from the TwinsUK Study, and dietary acid-base load. Body composition was calculated according to quartile of potential renal acid load and adjusted for age, physical activity, misreporting and smoking habit (FFM, FFMI also for fat mass) and additionally with percentage protein. RESULTS: Fat-free mass was positively associated with a more alkalinogenic dietary load (comparing quartile 1 vs 4: FFM 0.79 kg P < 0.001, FFM% 1.06 % <0.001, FFMI 0.24 kg/m² P = 0.002), and with the ratio of fruits and vegetables to potential acidogenic foods. CONCLUSIONS: We observed a small but significant positive association between a more alkaline diet and muscle mass indexes in healthy women that was independent of age, physical activity and protein intake equating to a scale of effect between a fifth and one half of the observed relationship with 10 years of age. Although protein is important for maintenance of muscle mass, eating fruits and vegetables that supply adequate amounts of potassium and magnesium are also relevant. The results suggest a potential role for diet in the prevention of muscle loss.

Body fat mass is a predictor of risk of osteoporotic fractures in women but not in men: a prospective population study.

OBJECTIVES: Obesity has generally been associated with higher bone density and lower fracture risk. However, weight-related indices of obesity may be related differently to health end-points, compared with fat-related indices (such as body fat distribution and fat mass), as they may capture different dimensions of obesity and the associated biological effects. The aim of this study was to examine the association between percentage body fat (%BF) and prospective risk of fracture. METHODS: The European Prospective Investigation into Cancer (EPIC) in Norfolk was a population-based prospective study. A total of 14 789 participants (6470 men, aged 42-82 years at baseline) were included. The main outcome measures were quantitative ultrasound of the heel and incident hip and any osteoporotic fractures. RESULTS: A total of 556 participants suffered a fracture (184 hip fractures) during 8.7 ± 0.8 years of follow-up. Risk of hip fracture decreased linearly with increasing %BF amongst women but not men. After adjustment for age, history of fracture, height, smoking, alcohol intake and heel broadband ultrasound attenuation (BUA), the hazard ratio (95% CI) for a 10% higher %BF on risk of hip fracture was 0.56 (0.39-0.79) in women and 0.92 (0.39-2.21) in men. The effect size in women was approximately equivalent to a difference of 5 years in age or 1 standard deviation (17 dB MHz(-1) ) increased BUA. A nonlinear negative association was also observed between %BF and risk of 'any type of fracture' amongst women but not men. CONCLUSIONS: The %BF appears to predict hip fracture risk in women with an effect size comparable to that of bone density as measured by heel ultrasound. This effect was not observed in men. Understanding the differences in relationships between different indices of obesity as well as sex differences may help to elucidate the metabolic and other underlying mechanisms involved in bone health and fracture risk.

Quantitative ultrasound of the heel and fracture risk assessment: an updated meta-analysis.

UNLABELLED: Meta-analysis of prospective studies shows that quantitative ultrasound of the heel using validated devices predicts risk of different types of fracture with similar performance across different devices and in elderly men and women. These predictions are independent of the risk estimates from hip DXA measures. INTRODUCTION: Clinical utilisation of heel quantitative ultrasound (QUS) depends on its power to predict clinical fractures. This is particularly important in settings that have no access to DXA-derived bone density measurements. We aimed to assess the predictive power of heel QUS for fractures using a meta-analysis approach. METHODS: We conducted an inverse variance random effects meta-analysis of prospective studies with heel QUS measures at baseline and fracture outcomes in their follow-up. Relative risks (RR) per standard deviation (SD) of different QUS parameters (broadband ultrasound attenuation [BUA], speed of sound [SOS], stiffness index [SI], and quantitative ultrasound index [QUI]) for various fracture outcomes (hip, vertebral, any clinical, any osteoporotic and major osteoporotic fractures) were reported based on study questions. RESULTS: Twenty-one studies including 55,164 women and 13,742 men were included in the meta-analysis with a total follow-up of 279,124 person-years. All four QUS parameters were associated with risk of different fracture. For instance, RR of hip fracture for 1 SD decrease of BUA was 1.69 (95% CI 1.43-2.00), SOS was 1.96 (95% CI 1.64-2.34), SI was 2.26 (95%CI 1.71-2.99) and QUI was 1.99 (95% CI 1.49-2.67). There was marked heterogeneity among studies on hip and any clinical fractures but no evidence of publication bias amongst them. Validated devices from different manufacturers predicted fracture risks with similar performance (meta-regression p values > 0.05 for difference of devices). QUS measures predicted fracture with a similar performance in men and women. Meta-analysis of studies with QUS measures adjusted for hip BMD showed a significant and independent association with fracture risk (RR/SD for BUA = 1.34 [95%CI 1.22-1.49]). CONCLUSIONS: This study confirms that heel QUS, using validated devices, predicts risk of different fracture outcomes in elderly men and women. Further research is needed for more widespread utilisation of the heel QUS in clinical settings across the world.

Optimal decision criterion for detecting change in bone mineral density during serial monitoring: a Bayesian approach.

UNLABELLED: Interpretation of change in serial bone densitometry using least significant change (LSC) may not lead to optimal decision making. Using the principles of Bayesian statistics and decision sciences, we developed the Optimal Decision Criterion (ODC) which resulted in 11-12.5% higher rate of correct classification compared with the LSC method. INTRODUCTION: The interpretation of change in serial bone densitometry emphasizes using least significant change (LSC) to distinguish between true changes and measurement error. METHODS: Using the principles of Bayesian statistics and decision sciences, we developed the optimal decision criterion (ODC) based on maximizing a 'utility' function that rewards the correct and penalizes the incorrect classification of change. The relationship between LSC and ODC is demonstrated using a clinical sample from the Manitoba Bone Density Program. RESULTS: Under certain conditions, it can be shown that using LSC at the 95% confidence level implicitly equates the benefit of 39 true positive diagnoses with the harm of one false positive classification of BMD change. ODC resulted in an 11% higher rate of correct classification for lumbar spine BMD change and a 12.5% better performance for classifying total hip BMD change compared with LSC with this method. CONCLUSIONS: ODC has the same clinical interpretation as LSC but with two major advantages: it can incorporate prior knowledge of the likely values of the true change and it can be fine-tuned based on the relative value placed on the correct and incorrect classifications. Bayesian statistics and decision sciences could potentially increase the yield of a BMD monitoring program.

Prolonged dual antiplatelet therapy in stable coronary disease: comparative observational study of benefits and harms in unselected versus trial populations.

OBJECTIVE:  To estimate the potential magnitude in unselected patients of the benefits and harms of prolonged dual antiplatelet therapy after acute myocardial infarction seen in selected patients with high risk characteristics in trials. DESIGN:  Observational population based cohort study. SETTING:  PEGASUS-TIMI-54 trial population and CALIBER (ClinicAl research using LInked Bespoke studies and Electronic health Records). PARTICIPANTS:  7238 patients who survived a year or more after acute myocardial infarction. INTERVENTIONS:  Prolonged dual antiplatelet therapy after acute myocardial infarction. MAIN OUTCOME MEASURES:  Recurrent acute myocardial infarction, stroke, or fatal cardiovascular disease. Fatal, severe, or intracranial bleeding. RESULTS:  1676/7238 (23.1%) patients met trial inclusion and exclusion criteria ("target" population). Compared with the placebo arm in the trial population, in the target population the median age was 12 years higher, there were more women (48.6% v 24.3%), and there was a substantially higher cumulative three year risk of both the primary (benefit) trial endpoint of recurrent acute myocardial infarction, stroke, or fatal cardiovascular disease (18.8% (95% confidence interval 16.3% to 21.8%) v 9.04%) and the primary (harm) endpoint of fatal, severe, or intracranial bleeding (3.0% (2.0% to 4.4%) v 1.26% (TIMI major bleeding)). Application of intention to treat relative risks from the trial (ticagrelor 60 mg daily arm) to CALIBER's target population showed an estimated 101 (95% confidence interval 87 to 117) ischaemic events prevented per 10 000 treated per year and an estimated 75 (50 to 110) excess fatal, severe, or intracranial bleeds caused per 10 000 patients treated per year. Generalisation from CALIBER's target subgroup to all 7238 real world patients who were stable at least one year after acute myocardial infarction showed similar three year risks of ischaemic events (17.2%, 16.0% to 18.5%), with an estimated 92 (86 to 99) events prevented per 10 000 patients treated per year, and similar three year risks of bleeding events (2.3%, 1.8% to 2.9%), with an estimated 58 (45 to 73) events caused per 10 000 patients treated per year. CONCLUSIONS:  This novel use of primary-secondary care linked electronic health records allows characterisation of "healthy trial participant" effects and confirms the potential absolute benefits and harms of dual antiplatelet therapy in representative patients a year or more after acute myocardial infarction.

Burden of hip fracture in Iran.

To measure the burden caused by hip fracture in Iran and to compare it with other parts of the world, we applied the Global Burden of Disease (GBD) method created by the World Health Organization. The GBD method uses disability-adjusted life years (DALY), which is comprised of years of life lost (YLL) and years of life lived with disability (YLD). To calculate YLD, incidence of hip fracture was obtained from the Iranian Multicenter Study on Accidental Injuries, a large-scale nationwide prospective study. Disability weights were applied to the remaining duration of disease. To calculate YLL, remaining years of potential life at any age at death were calculated using the standard life table. A discount rate of 3% and age weighting were applied. Hip fracture generated 16,708 DALYs, comprising 8,812 (52.7%) YLL and 7,896 (47.3%) YLD. Iran accounted for 0.85% of the global burden of hip fracture and 12.4% of the burden of hip fracture in the Middle East. The female to male ratio in Iran (1.1) was lower than the global (2.2) and the Middle Eastern (1.4) ratios and higher than the ratios in China and India (1.0 and 0.9, respectively). In conclusion, hip fracture is not as much a cause of disease burden in Iran as in the developed regions of the world. We recommend utilization of the standardized GBD method to calculate burden of osteoporosis in different countries and to set local priorities according to these measures.

Minimum sample size requirements for bone density precision assessment produce inconsistency in clinical monitoring.

INTRODUCTION: Detection of change during bone mineral density (BMD) monitoring is affected by test precision. The International Society of Clinical Densitometry (ISCD) recommends that each center determine precision error using repeat measurements in 30 subjects (or an equivalent method providing 30 degrees of freedom). METHODS: We hypothesized that this sample size may be too small for a robust precision estimate, which could affect the performance of BMD monitoring in clinical practice. Replicate measurements of the spine and total hip (198 spine and 193 hip scan pairs) were obtained (interval 6+/-5 days). The sample was randomly divided into six groups of 30 patients each. Root mean square standard deviation (RMS-SD in g/cm(2)) and coefficient of variation (RMS-CV in %) precision errors and corresponding 95% least significant change (LSC) were calculated for each group and the pooled sample. LSC cutoffs were applied to 1,420 individuals from the Manitoba Bone Density Program who had follow-up measurements on the same instrument (interval 21+/-9 months). While the pooled spine RMS-SD was 0.017 and pooled hip RMS-SD was 0.009 g/cm(2), sample sizes of 30 gave a range of RMS-SD point estimates from 0.012 to 0.021 for the spine and from 0.008 to 0.012 for the hip. RESULTS: When the respective LSC cutoffs were applied to the 1,420 follow-up scan pairs, the fraction of patients categorized with significant change in the spine varied from 20.7% to 46.0%; four of the six LSCs based upon 30 subjects gave fractions significantly different from the pooled LSC of 30.7%. Significant change fractions for the hip varied from 31.1% to 51.1%; two of the six LSCs based upon 30 subjects gave fractions significantly different from the pooled LSC of 40.1%. Similar results were obtained using relative precision errors. CONCLUSION: BMD precision studies using a sample size of 30 are insufficient to reliably characterize precision error or change during clinical monitoring.

Epidemiology of hip fracture in Iran: results from the Iranian Multicenter Study on Accidental Injuries.

INTRODUCTION: The incidence of hip fracture varies substantially between countries. As a result of improving life expectancy, the number of elderly people susceptible to hip fractures is increasing rapidly in the developing world. Little is known, however, about the epidemiology of hip fractures in the Middle Eastern countries. In this study, our objective was to estimate the incidence of hip fracture in Iran and compare it with other populations. METHODS: The data used were obtained from the Iranian Multicenter Study on Accidental Injuries, a large-scale population-based study conducted in nine provinces across the country. All of the hospitals in these provinces, which provide services to about 9.5 million people, were prospectively surveyed for any incident injury resulting from accidental events occurring in the study period of 135 days (4.5 months). All patients aged >or=50 with radiographically confirmed proximal femur fractures were included in this study. A total of 555 new cases of hip fracture (284 male, 271 female) were recorded during the study period. The annual incidence of hip fracture per 100,000 person-years was 115.2 (95% CI: 107.2-123.7) in men and 115.6 (95% CI: 107.4-124.3) in women; of these,73.2 and 89.2%, respectively, were fall-related fractures. The female-to-male ratios for fall-induced and total hip fracture rates were 1.2 and 1.0, respectively. RESULTS: The incidence rates increased exponentially after the age of 60 years in both genders and nearly tripled with each successive decade. When these results are compared to those of other studies, the Iranian age-standardized incidence rates of 127.3 (men) and 164.6 (women) per 100,000 person-years are considerably lower than those of all Western countries when standardized to data on the U.S. population in 2000. When compared with incidence rates reported for other Asian countries, those of Iranian females are the lowest next to China. CONCLUSION: The low incidence rate of hip fracture for older Iranian women may be the result of several potential factors related to genetic or lifestyle differences between Iranians and people of other countries. Further studies are required to investigate contributing factors in more detail.

Bone mineral density and estimated height loss based on patients' recalls.

INTRODUCTION: Height loss has been shown to be an indicator of incident vertebral fractures. However, the relationship between height loss and bone mineral density (BMD) in different skeletal regions, as well as the power of human memory in estimation of height loss across the life span, has not yet been established. Given that the variation in BMD between populations is substantially less than the variation in fracture risk, we studied the relationship between height loss based on patient's recalls and BMD in Iranian men and women of all ages. METHODS: Randomized clustered sampling from all regions of Tehran was performed to recruit the study population. Participants were asked about their maximum recalled previously measured height, if they were confident. In the 457 participants included, the difference between the participants' maximum recalled and current measured height was calculated. RESULT: L1-L4 lumbar BMD, femoral neck BMD, and young adjusted T-scores were significantly lower in the group of participants with estimated height reduction of greater than 5 cm. In simple linear regression analysis, height loss was a significant predictor of femoral neck T-score (standardized beta coefficient=-0.15; p0.003) and L1-L4 lumbar T-score (beta=-0.08; p0.048). After adjustment for age, gender, and weight, height loss remained a significant predictor for femoral neck T-score (beta=-0.078; p0 .043). In multivariate models for lumbar T-score, height loss was an independent predictor only in participants equal to or younger than 50 years of age (beta=-0.144; p0.033). CONCLUSION: Higher estimated height loss according to patients' recalls was an indicator of lower BMD in our sample. Especially in the femoral neck region, this factor might be considered as a substitute case-finding tool for low BMD. Considering relatively young nature of our study group and biological differences between populations, our findings need to be validated in future prospective studies.

Artificial neural networks in prediction of bone density among post-menopausal women.

Artificial neural networks (ANN) are promising tools in learning complex interplay of factors on a particular outcome. We performed this study to compare the predictive power of ANN and conventional methods in prediction of bone mineral density (BMD) in Iranian post-menopausal women. A database of 10 input variables from 2158 participants was randomly divided into training (1400), validation (150) and test (608) groups. Multivariate linear regression and ANN models were developed and validated on the training, and validation sets and outcomes (femoral neck and lumbar T-scores) were predicted and compared on the test group using different numbers of input variables. Results were evaluated by comparing the mean square of differences between predicted and reference values (non-central chi-square test) and by measuring area under the receiver operating characteristic curve (AUROC) around cut-off value of -2.5 for T-scores. For models with less than 3 input variables in femoral neck and 4 variables in spinal column, performance of regression and ANN models was almost the same. As more variables imported into models, ANN outperformed linear regression models. AUROC varied in 2 to 10 variable models as follows: for ANN in spine, from 0.709 to 0.774; linear models in spine, from 0.709 to 0.744; ANN in femoral neck, from 0.801 to 0.867; linear models in femoral neck, from 0.799 to 0.834. The ANN model performed better than five established patient selection tools in the test group. Superior performance of neural networks than linear models demonstrate their advantage especially in mass screening applications, when even a slight enhancement in performance results in significant decrease in number of misclassifications.