Katrine Hass Rubin

Risk assessment tools to identify women with increased risk of osteoporotic fracture: complexity or simplicity? A systematic review.

A huge number of risk assessment tools have been developed. Far from all have been validated in external studies, more of them have absence of methodological and transparent evidence, and few are integrated in national guidelines. Therefore, we performed a systematic review to provide an overview of existing valid and reliable risk assessment tools for prediction of osteoporotic fractures. Additionally, we aimed to determine if the performance of each tool was sufficient for practical use, and last, to examine whether the complexity of the tools influenced their discriminative power. We searched PubMed, Embase, and Cochrane databases for papers and evaluated these with respect to methodological quality using the Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS) checklist. A total of 48 tools were identified; 20 had been externally validated, however, only six tools had been tested more than once in a population‐based setting with acceptable methodological quality. None of the tools performed consistently better than the others and simple tools (i.e., the Osteoporosis Self‐assessment Tool [OST], Osteoporosis Risk Assessment Instrument [ORAI], and Garvan Fracture Risk Calculator [Garvan]) often did as well or better than more complex tools (i.e., Simple Calculated Risk Estimation Score [SCORE], WHO Fracture Risk Assessment Tool [FRAX], and Qfracture). No studies determined the effectiveness of tools in selecting patients for therapy and thus improving fracture outcomes. High‐quality studies in randomized design with population‐based cohorts with different case mixes are needed.

Comparison of different screening tools (FRAX®, OST, ORAI, OSIRIS, SCORE and age alone) to identify women with increased risk of fracture. A population-based prospective study

PURPOSE To compare the power of FRAX® without bone mineral density (BMD) and simpler screening tools (OST, ORAI, OSIRIS, SCORE and age alone) in predicting fractures. METHODS This study was a prospective, population-based study performed in Denmark comprising 3614 women aged 40-90 years, who returned a questionnaire concerning items on risk factors for osteoporosis. Fracture risk was calculated using the different screening tools (FRAX®, OST, ORAI, OSIRIS and SCORE) for each woman. The women were followed using the Danish National Register registering new major osteoporotic fractures during 3 years, counting only the first fracture per person. Area under the receiver operating characteristic curve (ROC) and statistics and Harrells index were calculated. Agreement between the tools was calculated by kappa statistics. RESULTS A total of 4% of the women experienced a new major osteoporotic fracture during the follow-up period. There were no differences in the area under the curve (AUC) values between FRAX® and the simpler tools; AUC values between 0.703 and 0.722 (p = 0.86). Also, Harrells C values were very similar between the tools. Agreement between the tools was modest. CONCLUSION During 3 years follow-up FRAX® did not perform better in the fracture risk prediction compared with simpler tools such as OST, ORAI, OSIRIS, SCORE or age alone in a screening scenario where BMD was not measured. These findings suggest that simpler models based on fewer risk factors, which would be easier to use in clinical practice by the GP or the patient herself, could just as well as FRAX® be used to identify women with increased risk of fracture. SUMMARY Comparison of FRAX® and simpler screening tools (OST, ORAI, OSIRIS, SCORE) in predicting fractures indicate that FRAX® did not perform better in fracture risk prediction compared with the simpler tools or even age alone in a screening scenario without bone mineral density assessment.

Morbidity and medicine prescriptions in a nationwide Danish population of patients diagnosed with polycystic ovary syndrome

OBJECTIVE The prevalence of type 2 diabetes is increased in polycystic ovary syndrome (PCOS), but the prevalence of other diseases is not clarified. We aimed to investigate morbidity and medicine prescriptions in PCOS. DESIGN A National Register-based study. METHODS Patients with PCOS (PCOS Denmark and an embedded cohort; PCOS Odense University Hospital (OUH)) and one control population. Premenopausal women with PCOS underwent clinical and biochemical examination (PCOS OUH, n=1217). PCOS Denmark (n=19 199) included women with PCOS in the Danish National Patient Register. Three age-matched controls were included per patient (n=57 483). MAIN OUTCOME MEASURES Diagnosis codes and filled prescriptions. RESULTS The mean (range) age of the PCOS Denmark group and controls was 30.6 (12-60) years. Patients in PCOS Denmark had higher Charlson index, higher prevalence of diabetes, dyslipidemia, and hypertension than controls. PCOS was associated with a two times increased risk of stroke and thrombosis, whereas the risk of other cardiovascular diseases was not increased. Thyroid disease, asthma, migraine, and depression were more prevalent in PCOS Denmark vs controls, whereas fractures were rarer. Infertility was increased in patients compared with controls, but the mean number of births was higher in PCOS. Medicine prescriptions within all diagnosis areas were significantly higher in PCOS patients than in controls.In PCOS OUH, polycystic ovaries (PCO) and irregular menses were associated with a more adverse metabolic risk profile, but individual Rotterdam criteria were not associated with cardiometabolic diagnoses. CONCLUSION Cardiometabolic and psychiatric morbidity were significantly increased in a Danish population with PCOS. Medical diseases are frequent also in young patients with PCOS.

A review of lifestyle, smoking and other modifiable risk factors for osteoporotic fractures

Although many strong risk factors for osteoporosis-such as family history, fracture history and age-are not modifiable, a number of important risk factors are potential targets for intervention. Thus, simple, non-pharmacological intervention in patients at increased risk of osteoporotic fractures could include reduction of excessive alcohol intake, smoking cessation, adequate nutrition, patient education, daily physical activity and a careful review of medications that could increase the risk of falls and fractures. There remains, however, an unmet need for high-quality intervention studies in most of these areas.

Characteristics of patients who suffer major osteoporotic fractures despite adhering to alendronate treatment: a National Prescription registry study

SummaryAntiresorptive treatment reduces the risk of fractures, but most patients remain at elevated risk. We used health registers to identify predictors of new major osteoporotic fractures in patients adhering to alendronate. Risk factors showed a different pattern than in the general population and included dementia, ulcer disease, and Parkinson’s disease.IntroductionAntiresorptives reduce the excess risk of fractures in patients with osteoporosis, but most patients remain at elevated risk. In some countries, patients must sustain fractures while on bisphosphonate (BP) treatment to qualify for more expensive treatment. It is unclear if patients who fracture on BP can be viewed as a distinct subgroup.MethodsThe National Prescription registry was used to identify 38,088 new alendronate users. The outcome was major osteoporotic fractures 6+ months after filling the first prescription in patients with a medication possession ratio > 80 %.ResultsOne thousand and seventy-two (5.5 %) patients sustained major osteoporotic fractures. The risk increased with age and was lower in men. The most important risk factor was the number of comedications (hazard ratio (HR) 1.04, 95 % CI 1.03–1.06, for each drug). Dementia (HR 1.81, 95 % CI 1.18–2.78), prior fracture (one: HR 1.17, 95 % CI 1.02–1.34; multiple: HR 1.34, 95 % CI 1.08–1.67), and ulcer disease (HR 1.45, 95 % CI 1.04–2.03) also increased the risk. Diabetes did not influence fracture risk, nor did rheumatic disorders. The risk was lower in glucocorticoid users (HR 0.78, 95 % CI 0.65–0.93).ConclusionRisk factors while adhering to BP show a somewhat different pattern than that of the general population and FRAX. Ulcer disease and dementia may impair the ability to use the medications correctly. Though this is an observational study and associations may not be causal, it may be prudent to include dementia, ulcer disease, and Parkinson’s disease to capture the risk of fractures on treatment. Lower risk in patients treated with glucocorticoids and in men probably reflects a lower treatment threshold related to guidelines.

Fracture risk assessed by Fracture Risk Assessment Tool (FRAX) compared with fracture risk derived from population fracture rates

Purpose: To evaluate the performance of the Swedish version of Fracture Risk Assessment Tool (FRAX)) without bone mass density (BMD) in a Danish population to examine the possibility of applying this version to Danish women. Methods: From the Danish National Register of social security numbers, we randomly selected 5000 women living in the region of Southern Denmark aged 40—90 years to receive a mailed questionnaire concerning risk factors for osteoporosis based on FRAX. The predicted 10-year probability of hip fractures was calculated for each woman returning a complete questionnaire using the Swedish version of FRAX. The observed 10-year hip fracture risk was also calculated for each woman using age-specific hip fracture rates from the National Hospital Discharge Register and National survival tables. Results: A total of 4194 (84%) women responded to the questionnaire and 3636 (73%) gave complete information and were included in the analysis. Using FRAX, the predicted 10-year fracture risk was 7.6%, ranging from 0.3 to 25.0% at the age of 41—50 and 81—90, respectively, while the corresponding observed fracture risk was 7.6%, ranging from 0.4 to 24.0%, respectively and not significantly different from the predicted risk (p = 0.92). Conclusions: The Swedish version of FRAX without BMD is applicable to Danish women.

Diagnostic devices for osteoporosis in the general population: A systematic review

INTRODUCTION A diagnostic gap exists in the current dual photon X-ray absorptiometry (DXA) based diagnostic approach to osteoporosis. Other diagnostic devices have been developed, but no comprehensive review concerning the applicability of these diagnostic devices for population-based screening have been performed. MATERIAL AND METHODS A systematic review of Embase, Medline and the Cochrane Central Register for Controlled Trials was performed for population-based studies that focused on technical methods that could either indicate bone mineral density (BMD) by DXA, substitute for DXA in prediction of fracture risk, or that could have an incremental value in fracture prediction in addition to DXA. Quality of included studies was rated by QUADAS 2. RESULTS Many other technical devices have been tested in a population-based setting. Five studies aiming to indicate BMD and 17 studies aiming to predict fractures were found. Overall, the latter studies had higher methodological quality. The highest number of studies was found for quantitative ultrasound (QUS). The ability to indicate BMD or predict fractures was moderate to minor for all examined devices, using reported area under the curve (AUC) of Receiver Operating Characteristic curves values as standard. CONCLUSIONS Of the methods assessed, only QUS appears capable of perhaps replacing DXA as standalone examination in the future whilst radiographic absorptiometry could provide important information in areas with scarcity of DXA. QUS may be of added value even after DXA has been performed. Evaluation of proposed cutoff-values from population-based studies in separate population-based cohorts is still lacking for most examination devices.

Development and Risk Factors of Type 2 Diabetes in a Nationwide Population of Women With Polycystic Ovary Syndrome

Objective Polycystic ovary syndrome (PCOS) is associated with insulin resistance and obesity. Prospective population-based data regarding development and possible predictors of type 2 diabetes (T2D) in PCOS are limited. Design National Patient Register-based study. Methods Patients with PCOS [PCOS Denmark and embedded cohort, PCOS Odense University Hospital (OUH)] and a control population with no previous diagnosis of T2D. PCOS OUH (N = 1,162) included premenopausal women with PCOS and standardized clinical and biochemical examination. PCOS Denmark (N = 18,477) included women with PCOS in the Danish National Patient Register. Three age-matched controls were included per patient (N = 54,680). Main outcome T2D events according to diagnosis codes and filled medicine prescriptions. Results The median (quartiles) follow-up was 11.1 (6.9 to 16.0) years. The hazard ratio (HR) with 95% confidence interval (CI) for development of T2D in PCOS Denmark was HR = 4.0 (95% CI, 3.7 to 4.3; P < 0.001), and the total event rate of T2D was 8.0 per 1000 person years in PCOS Denmark vs 2.0 per 1000 person years in controls (P < 0.001). The median age at diagnosis of T2D was 31 (26 to 37) years in PCOS Denmark vs 35 (27 to 44) years in controls (P < 0.001). In multiple regression analyses, body mass index, glycated hemoglobin, fasting blood glucose, 2-hour blood glucose, homeostasis model assessment of insulin resistance, and triglycerides were positively associated with development of T2D, whereas higher number of births was negatively associated with development of T2D. Conclusion The event rate of T2D was higher in PCOS compared with controls, and T2D was diagnosed at a younger age.

Incidence and Predictors of Multiple Fractures Despite High Adherence to Oral Bisphosphonates: A Binational Population-Based Cohort Study.

Oral bisphosphonates (BPs) are highly effective in preventing fractures and are recommended first‐line therapies for patients with osteoporosis. We identified the incidence and predictors of oral BP treatment failure, defined as the incidence of two or more fractures while on treatment (≥2 FWOT) among users with high adherence. Fractures were considered from 6 months after treatment initiation and up to 6 months after discontinuation. Data from computerized records and pharmacy invoices were obtained from Sistema d‘Informació per al Desenvolupament de l‘Investigació en Atenció Primària (SIDIAP; Catalonia, Spain) and Danish Health Registries (Denmark) for all incident users of oral BPs in 2006‐2007 and 2000‐2001, respectively. Fine and Gray survival models using backward‐stepwise selection (p‐entry 0.049; p‐ exit 0.10) and accounting for the competing risk of therapy cessation were used to identify predictors of ≥2 FWOT among patients having persisted with treatment ≥6 months with overall medication possession ratio (MPR) ≥80%. Incidence of ≥2 FWOT was 2.4 (95% confidence interval [CI], 1.8 to 3.2) and 1.7 (95% CI, 1.2 to 2.2) per 1000 patient‐years (PYs) within Catalonia and Denmark, respectively. Older age was predictive of ≥2 FWOT in both Catalonian and Danish cohorts: subhazard ratio (SHR) = 2.28 (95% CI, 1.11 to 4.68) and SHR = 2.61 (95% CI, 0.98 to 6.95), respectively, for 65 to <80 years; and SHR = 3.19 (95% CI, 1.33 to 7.69) and SHR = 4.88 (95% CI, 1.74 to 13.7), respectively, for ≥80 years. Further significant predictors of ≥2 FWOT identified within only one cohort were dementia, SHR = 4.46 (95% CI, 1.02 to 19.4) (SIDIAP); and history of recent or older fracture, SHR = 3.40 (95% CI, 1.50 to 7.68) and SHR = 2.08 (95% CI: 1.04‐4.15), respectively (Denmark). Even among highly adherent users of oral BP therapy, a minority sustain multiple fractures while on treatment. Older age was predictive of increased risk within both study populations, as was history of recent/old fracture and dementia within one but not both populations. Additional and/or alternative strategies should be investigated for these patients.

Fracture Risk Prediction Using Phalangeal Bone Mineral Density or FRAX®?—A Danish Cohort Study on Men and Women

In this prospective study, we investigated the ability of Fracture Risk Assessment Tool (FRAX), phalangeal bone mineral density (BMD), and age alone to predict fractures using data from a Danish cohort study, Danish Health Examination Survey 2007-2008, including men (n = 5206) and women (n = 7552) aged 40-90 yr. Data were collected using a self-administered questionnaire and by phalangeal BMD measurement. Information on incident and prevalent fractures, rheumatoid arthritis, and secondary osteoporosis was retrieved from the Danish National Patient Registry. Survival analyses were used to examine the association between low, intermediate, and high risk by phalangeal T-score or FRAX and incident fractures, and receiver operating characteristic curves were obtained. Mean follow-up time was 4.3 yr, and a total of 395 persons (3.1%) experienced a fracture during follow-up. The highest rate of major osteoporotic fractures was observed in persons with a high combined risk (FRAX ≥20% and T-score ≤-2.5; women: 32.7 and men: 27.6 per 1000 person-yr). This group also had the highest risk of hip fractures (women: 8.1 and men: 7.2 per 1000 person-yr). FRAX and T-score in combination analyzed as continuous variables performed overall best in the prediction of major osteoporotic fractures. In predicting hip fractures, there was a tendency of T-score performing worse than the other methods.