Comparative risk of acute myocardial infarction for anti-osteoporosis drugs in primary care: a meta-analysis of propensity-matched cohort findings from the UK Clinical Practice Research Database and the Catalan SIDIAP Database.

The aim of this study was to evaluate the risk of acute myocardial infarction in patients taking osteoporosis medication. Patients were taken from the SIDIAP or CPRD database and were matched using propensity scores. Patients with diabetes and chronic kidney disease taking SERMs were at an increased risk. The results favour the cardiovascular safety of alendronate as a first-line choice for osteoporosis treatment. INTRODUCTION: This study aims to evaluate the comparative safety of anti-osteoporosis drugs based on the observed risk of acute myocardial infarction while on treatment in a primary care setting. METHODS: This is a propensity-matched cohort study and meta-analysis. This study was conducted in two primary care record databases covering UK NHS (CPRD) and Catalan healthcare (SIDIAP) patients during 1995-2014 and 2006-2014, respectively. The outcome was acute myocardial infarction while on treatment. Users of alendronate (reference group) were compared to those of (1) other oral bisphosphonates (OBP), (2) strontium ranelate (SR), and (3) selective oestrogen receptor modulator (SERM), after matching on baseline characteristics (socio-demographics, fracture risk factors, comorbidities, and concomitant drug use) using propensity scores. Multiple imputation was used to handle missing data on confounders and competing risk modelling for the calculation of relative risk (sub-distribution hazard ratios (SHR)) according to therapy. Country-specific data were analysed individually and meta-analysed. RESULTS: A 10% increased risk of acute myocardial infarction was found in users of other bisphosphonates as compared to alendronate users within CPRD. The meta-analysis of CPRD and SIDIAP results showed a 9% increased risk in users of other bisphosphonate as compared to alendronate users. Sensitivity analysis showed SERMS users with diabetes and chronic kidney disease were at an elevated risk. CONCLUSIONS: This study provides additional data on the risk of acute myocardial infarction in patients receiving osteoporosis treatment. The results favour the cardiovascular safety of alendronate as a first-line choice for osteoporosis treatment.

The risk of new fragility fractures in patients with chronic kidney disease and hip fracture-a population-based cohort study in the UK.

Chronic kidney disease (CKD) is a risk factor for fractures. However, in hip fracture patients, CKD G3-G5 was associated with a higher mortality risk and not associated with a higher risk of subsequent non-hip fractures compared to eGFR > 60 ml/min. The higher mortality risk may, as competing risk, explain our findings. INTRODUCTION: Chronic kidney disease (CKD) is a known risk factor for fragility fractures. Patients aged 50+ with a recent fragility fracture have an increased risk of subsequent fractures. Our aim was to evaluate the association between CKD stages G3-G5 versus estimated glomerular filtration rate (eGFR) > 60 ml/min and the risk of a new non-hip fracture or fragility fracture in patients with a first hip fracture. METHODS: Population-based cohort study using the UK general practices in the Clinical Practice Research Datalink. Associations between CKD stage and first subsequent fracture were determined using Cox proportional hazard analyses to estimate hazard ratios (HRs). To explore the potential competing risk of mortality, cause-specific (cs) HRs for mortality were estimated. RESULTS: CKD G3-G5 was associated with a lower risk of any subsequent non-hip fracture (HR: 0.90, 95%CI: 0.83-0.97), but not with the risk of subsequent major non-hip fragility fracture. CKD G3-G5 was associated with a higher mortality risk (cs-HR: 1.05, 95%CI: 1.01-1.09). Mortality risk was 1.5- to 3-fold higher in patients with CKD G4 (cs-HR: 1.50, 95%CI: 1.38-1.62) and G5 (cs-HR: 2.93, 95%CI: 2.48-3.46) compared to eGFR > 60 ml/min. CONCLUSIONS: The risk of a subsequent major non-hip fragility fractures following hip fracture was not increased in patients with CKD G3-G5 compared to eGFR > 60 ml/min. Mortality risk was higher in both hip fracture and non-hip fracture patients with CKD G4 and G5. The higher mortality risk may, as competing risk, explain our main finding of no increased or even decreased subsequent fracture risk after a hip fracture in patients with CKD G3-G5.

Risk of venous thromboembolism among users of different anti-osteoporosis drugs: a population-based cohort analysis including over 200,000 participants from Spain and the UK.

The venous thromboembolism risk among anti-osteoporotics is unknown. In this primary care study, the risk with other bisphosphonates [1.05 (0.94-1.18) and 0.96 (0.78-1.18)], strontium [0.90 (0.61-1.34) and 1.19 (0.82-1.74)], in the UK and Spain respectively, and denosumab [1.77 (0.25-12.66)] and teriparatide [1.27 (0.59-2.71)] in Spain, did not differ versus alendronate. INTRODUCTION: Most of the known adverse drug reactions described for anti-osteoporosis medication (AOM) have been described in studies comparing AOM users to non-users. We aimed to compare the risk of venous thromboembolism (VTE) among incident users of different AOM compared to alendronate (first line therapy). METHODS: Two cohort studies were performed using data from the UK (CPRD) and Spain (BIFAP) primary care records separately. All patients aged ≥ 50 years with at least 1 year of data available and a new prescription or dispensation of AOM (date for therapy initiation) during 2000-2014 (CPRD) or 2001-2013 (BIFAP) were included. Users of raloxifene/bazedoxifene were excluded from both databases. Five exposure cohorts were identified according to first treatment: (1) alendronate, (2) other bisphosphonates, (3) strontium ranelate, (4) denosumab, and (5) teriparatide. Participants were followed from the day after therapy initiation to the earliest of a treated VTE (cases), end of AOM treatment (defined by a refill gap of 180 days), switching to an alternative AOM, drop-out, death, or end of study period. Incidence rates of VTE were estimated by cohort. Adjusted hazard ratios (HR 95%CI) were estimated according to drug used. RESULTS: Overall, 2035/159,209 (1.28%) in CPRD and 401/83,334 (0.48%) in BIFAP had VTE. Compared to alendronate, adjusted HR of VTE were 1.05 (0.94-1.18) and 0.96 (0.78-1.18) for other bisphosphonates, and 0.90 (0.61-1.34) and 1.19 (0.82-1.74) for strontium in CPRD and BIFAP, respectively; 1.77 (0.25-12.66) for denosumab and 1.27 (0.59-2.71) for teriparatide in BIFAP. CONCLUSIONS: VTE risk during AO therapy did not differ by AOM drug use. Our data does not support an increased risk of VTE associated with strontium ranelate use in the community.

The epidemiology of mortality after fracture in England: variation by age, sex, time, geographic location, and ethnicity.

One-year mortality following a fracture was greater for men compared to women, varied markedly between regions in England with the lowest rates in the London region, and was higher among black women compared to white women. The excess in mortality did not change during the study period. INTRODUCTION: Fractures are associated with increased mortality. With the shift towards an increasingly elderly demography, and so increasing numbers of fractures, the impact of such events on mortality is of key public health importance. Therefore, we aimed to present up-to-date mortality rates following fracture in England. METHODS: This was a population-based study within the Clinical Practice Research Datalink, linked to death certificates (1 January 2001 to 31 December 2011). Subjects were followed from their first fracture (hip, wrist, humerus, clinical spine, ribs, or pelvis) until death for up to 1 year. Rate ratios (RRs) were estimated for 1-year mortality, stratified by sex, 5-year age categories, ethnicity, and geographical region. Excess mortality was presented as standardized mortality ratios (SMRs). RESULTS: One-year mortality following fracture increased with age and was higher for men than women. Black women (RR 1.77; 95 % CI 1.00-3.12) and women of "other" ethnicity (RR 1.59, 95 % CI 1.16-2.16) were at higher risk of death when compared to white women. Mortality was higher among women in almost all regions when compared to the London region, with the highest risk in the East Midlands (37 % higher). The 1-year mortality risk was more than 3-fold higher after fracture as compared to the general population (adjusted SMR: 3.15, 95 % CI 3.09-3.26) and did not change during the study period. Major causes of death were neoplasms, respiratory diseases, and circulatory diseases. CONCLUSION: This study provides up-to-date mortality outcomes following fracture in England and will aid allocation of healthcare provision to those at greatest need.

Secular trends in fracture incidence in the UK between 1990 and 2012.

We studied sex-specific incidence rates in a population 50 years or older in the UK. In the period of 1990-2012, the overall rate of fracture did not change, but there were marked secular alterations in the rates of individual fracture types, particularly hip and spine fractures in the elderly. INTRODUCTION: There is increasing evidence of secular changes in age- and sex- adjusted fracture incidence globally. Such observations broadly suggest decreasing rates in developed countries and increasing rates in transitioning populations. Since altered fracture rates have major implications for healthcare provision and planning, we investigated secular changes to age- and sex-adjusted fracture risk amongst the UK population aged 50 years or above from 1990 till 2012. METHODS: We undertook a retrospective observational study using the Clinical Practice Research Datalink (CPRD), which contains the health records of 6.9 % of the UK population. Site-specific fracture incidence was calculated by calendar year for men and women separately, with fracture type categorised according to ICD-9 classification. Linear regression analysis was used to calculate mean annualised change in absolute incidence. For presentational purposes, mean rates in the first 5 years and last 5 years of the period were calculated. RESULTS: Overall fracture incidence was unchanged in both women and men from 1990 to 2012. The incidence of hip fracture remained stable amongst women (1990-1994 33.8 per 10,000 py; 2008-2012 33.5 per 10,000 py; p trend annualised change in incidence = 0.80) but rose in men across the same period (10.8 to 13.4 per 10,000 py; p = 0.002). Clinical vertebral fractures became more common in women (8.9 to 11.8 per 10,000 py; p = 0.005) but remained comparable in men (4.6 to 5.9 per 10,000 py; p = 0.72). Similarly, the frequency of radius/ulna fractures did not change in men (9.6 to 9.6 per 10,000 py; p = 0.25), but, in contrast, became less frequent in women (50.4 to 41.2 per 10,000 py; p = 0.001). Secular trends amongst fractures of the carpus, scapula, humerus, foot, pelvis, skull, clavicle, ankle, patella, and ribs varied according to fracture site and sex. CONCLUSION: Although overall sex-specific fracture incidence in the UK population 50 years or over appears to have remained stable over the last two decades, there have been noticeable changes in rates of individual fracture types. Given that the impact of a fracture on morbidity, mortality, and health economy varies according to fracture site, these data inform the provision of healthcare services in the UK and elsewhere.

Risk of vertebral and non-vertebral fractures in patients with sarcoidosis: a population-based cohort.

UNLABELLED: In this retrospective cohort study using the Clinical Practice Research Datalink (CPRD), patients with sarcoidosis have an increased risk of clinical vertebral fractures and when on recent treatment with oral glucocorticoids, also an increased risk of any fractures and osteoporotic fractures. INTRODUCTION: Sarcoidosis is a chronic inflammatory disease, in which fragility fractures have been reported despite normal BMD. The aim of this study was to assess whether patients with sarcoidosis have an increased risk of clinical fractures compared to the general population. METHODS: A retrospective cohort study was conducted using the CPRD. All patients with a CPRD code for sarcoidosis between January 1987 and September 2012 were included. Cox proportional hazards models were used to derive adjusted relative risks (RRs) of fractures in all sarcoidosis patients compared to matched controls, and within the sarcoidosis group according to use and dose of systemic glucocorticoids. RESULTS: Five thousand seven hundred twenty-two sarcoidosis patients (mean age 48.0 years, 51 % females, mean follow-up 6.7 years) were identified. Compared to 28,704 matched controls, the risk of any fracture was not different in patients with sarcoidosis. However, the risk of clinical vertebral fractures was significantly increased (adj RR 1.77; 95 % CI 1.06-2.96) and the risk of non-vertebral fractures was decreased although marginally significant (adj RR 0.87; 95 % CI 0.77-0.99). Compared to sarcoidosis patients not taking glucocorticoids, recent use of systemic glucocorticoids was associated with an increased risk of any fracture (adj RR 1.50; 95 % CI 1.20-1.89) and of an osteoporotic fracture (adj RR 1.47; 95 % CI 1.07-2.02). CONCLUSIONS: Patients with sarcoidosis have an increased risk of clinical vertebral fractures, and when using glucocorticoid therapy, an increased risk of any fractures and osteoporotic fractures. In contrast, the risk of non-vertebral fractures maybe decreased. Further investigation is needed to understand the underlying mechanisms of these contrasting effects on fracture risk.

Anti-osteoporosis drug prescribing after hip fracture in the UK: 2000-2010.

UNLABELLED: The probability of initiating with anti-osteoporosis therapy increased from 7 % in 2000 to 46 % in 2010. This improvement was greater for patients over the age of 75 years. Men, those overweight, having dementia or exposed to antipsychotics, sedatives/hypnotics or opioid analgesics were significantly less likely to receive anti-osteoporosis drugs. INTRODUCTION: The objective of this study was to examine trends and determinants of anti-osteoporosis drug prescribing after hip fracture in the UK between 2000 and 2010. METHODS: Data were extracted from the UK Clinical Practice Research Datalink for patients ≥50 years who had a first hip fracture between 2000 and 2010 and who did not currently (≤6 months prior) receive anti-osteoporosis drugs (bisphosphonates, strontium ranelate, parathyroid hormone, calcitonin and raloxifene) (n = 27,542). The cumulative incidence probability of being prescribed anti-osteoporosis drugs within 1 year after hip fracture was estimated by Kaplan-Meier life-table analyses. Determinants for treatment initiation were estimated by Cox proportional hazards models. RESULTS: The probability of being prescribed any anti-osteoporosis drug after hip fracture increased from 7 % in 2000 to 46 % in 2010. This trend was more marked in patients ≥75 years. The increase in prescribing of anti-osteoporosis drugs was complemented by a similar increase in vitamin D/calcium provision. Cumulative incidence of receiving anti-osteoporosis therapy was greater at any given point in time in women (8 % in 2000, 51 % in 2010) compared to men (4 % in 2000, 34 % in 2010). In addition to male gender, multivariable Cox regression identified reduced likelihood of receiving anti-osteoporosis drugs for those being overweight, having dementia and exposed to psychotropic drugs (antipsychotics, sedatives/hypnotics) or opioid analgesics. CONCLUSION: Although the prescribing of anti-osteoporosis drugs after hip fracture has increased substantially since 2000, the overall rate remained inadequate, particularly in men. With the continuing increase in the absolute number of hip fractures, further research should be made into the barriers to optimise osteoporosis management.

Long-term exposure to outdoor air pollution and the incidence of chronic obstructive pulmonary disease in a national English cohort.

OBJECTIVES: The role of outdoor air pollution in the incidence of chronic obstructive pulmonary disease (COPD) remains unclear. We investigated this question using a large, nationally representative cohort based on primary care records linked to hospital admissions. METHODS: A cohort of 812 063 patients aged 40-89 years registered with 205 English general practices in 2002 without a COPD diagnosis was followed from 2003 to 2007. First COPD diagnoses recorded either by a general practitioner (GP) or on admission to hospital were identified. Annual average concentrations in 2002 for particulate matter with an aerodynamic diameter <10 µm (PM10) and <2.5 µm (PM2.5), nitrogen dioxide (NO2), ozone and sulfur dioxide (SO2) at 1 km(2) resolution were estimated from emission-based dispersion models. Hazard ratios (HRs) per interquartile range change were estimated from Cox models adjusting for age, sex, smoking, body mass index and area-level deprivation. RESULTS: 16 034 participants (1.92%) received a COPD diagnosis from their GP and 2910 participants (0.35%) were admitted to hospital for COPD. After adjustment, HRs for GP recorded COPD and PM10, PM2.5 and NO2 were close to unity, positive for SO2 (HR=1.07 (95% CI 1.03 to 1.11) per 2.2 µg/m(3)) and negative for ozone (HR=0.94 (0.89 to 1.00) per 3 µg/m(3)). For admissions HRs for PM2.5 and NO2 remained positive (HRs=1.05 (0.98 to 1.13) and 1.06 (0.98 to 1.15) per 1.9 µg/m(3) and 10.7 µg/m(3), respectively). CONCLUSIONS: This large population-based cohort study found limited, inconclusive evidence for associations between air pollution and COPD incidence. Further work, utilising improved estimates of air pollution over time and enhanced socioeconomic indicators, is required to clarify the association between air pollution and COPD incidence.

Use of electronic healthcare records in large-scale simple randomized trials at the point of care for the documentation of value-based medicine.

A solid foundation of evidence of the effects of an intervention is a prerequisite of evidence-based medicine. The best source of such evidence is considered to be randomized trials, which are able to avoid confounding. However, they may not always estimate effectiveness in clinical practice. Databases that collate anonymized electronic health records (EHRs) from different clinical centres have been widely used for many years in observational studies. Randomized point-of-care trials have been initiated recently to recruit and follow patients using the data from EHR databases. In this review, we describe how EHR databases can be used for conducting large-scale simple trials and discuss the advantages and disadvantages of their use.

Application of routine electronic health record databases for pharmacogenetic research.

Inter-individual variability in drug responses is a common problem in pharmacotherapy. Several factors (non-genetic and genetic) influence drug responses in patients. When aiming to obtain an optimal benefit-risk ratio of medicines and with the emergence of genotyping technology, pharmacogenetic studies are important for providing recommendations on drug treatments. Advances in electronic healthcare information systems can contribute to increasing the quality and efficiency of such studies. This review describes the definition of pharmacogenetics, gene selection and study design for pharmacogenetic research. It also summarizes the potential of linking pharmacoepidemiology and pharmacogenetics (along with its strengths and limitations) and provides examples of pharmacogenetic studies utilizing electronic health record databases.

Increase in prophylaxis of glucocorticoid-induced osteoporosis by pharmacist feedback: a randomised controlled trial.

UNLABELLED: The aim of this study was to determine whether feedback by pharmacists to prescribers of patients eligible for glucocorticoid-induced osteoporosis prophylaxis would stimulate the prescribing of osteoporosis prophylaxis. The intervention did not significantly increase the prescribing of bisphosphonates in the total study population, but a significant increase was seen in men and in the elderly. However, the proportion of bisphosphonate-treated patients remained low. INTRODUCTION: The aim of this study was to determine whether feedback by pharmacists to prescribers of patients eligible for glucocorticoid-induced osteoporosis prophylaxis (GIOP) would stimulate the implementation of the Dutch GIOP guideline. METHODS: This randomised controlled trial included 695 patients who were dispensed ≥675 mg prednisone equivalents without a concomitant bisphosphonate prescription within 6 months before baseline. Pharmacists were asked to contact the physicians of GIOP-eligible patients in the intervention group to suggest osteoporosis prophylaxis. The primary endpoint was a bisphosphonate prescription. Secondary endpoints were a prescription of calcium supplements, vitamin D or any prophylactic osteoporosis drug (bisphosphonate, calcium supplements, vitamin D). RESULTS: The group assigned to the intervention was slightly younger than the control group (68.7 ± 15.4 vs. 65.9 ± 16.9 years, p = 0.02) and used hydrocortisone more often (7.0% vs. 3.1%, p = 0.02). Within 6 months, the intervention did not significantly increase the prescribing of bisphosphonates (11.4% after intervention vs. 8.0% for controls; hazard ratio [HR] 1.47, 95% confidence interval [CI] 0.91-2.39). However, subgroup analyses showed a significant increase for the primary endpoint in men (12.8% vs. 5.1%, HR 2.53, 95% CI 1.11-5.74) and patients ≥70 years (13.4% vs. 4.9%, HR 2.88, 95% CI 1.33-6.23). The prescribing of calcium and vitamin D was not significantly altered. CONCLUSION: This study showed that active identification of patients eligible for GIOP by pharmacists did not significantly increase the prescribing of bisphosphonates in the total study population, but there was an increase in men and the elderly. However, the proportion of GIOP-treated patients remained low.

Risk of fracture in patients with Guillain-Barré syndrome.

UNLABELLED: The aim of this study was to evaluate fracture risk in patients with Guillain-Barré syndrome (GBS). No association with risk of fracture was observed for GBS patients compared with controls. Only GBS patients using pain treatment had a doubled risk of fracture. INTRODUCTION: Symptoms of Guillain-Barré syndrome (GBS) may vary from mild difficulty in walking to complete paralysis, which may increase the risk of fractures. Therefore, the aim of this study was to evaluate fracture risk in patients with GBS. METHODS: We conducted a retrospective cohort study using the UK Clinical Practice Research Datalink (1987-2012). Each patient with GBS was matched by year of birth, sex, and practice, up to six patients without a history of GBS. Outcome measure was any fracture. RESULTS: There were no associations between GBS and any fracture, adjusted hazard ratio (AHR) 1.01 (95 % confidence interval [CI] 0.77-1.33), or osteoporotic fracture, AHR 0.76 (95 % CI 0.50-1.17), compared with controls. Stratification to gender, age, and duration since diagnosis did not show an association either. Only for GBS patients using pain treatment, risk of fracture was doubled AHR 1.97 (95 % confidence CI 1.21-3.21) compared with controls. The risk of fracture in GBS patients exposed to pain treatment was equivalent to risk of fracture among controls exposed to pain treatment. CONCLUSIONS: No association with risk of fracture was observed for GBS patients compared with controls. Only GBS patients using pain treatment had a doubled risk of fracture, but their risk was equivalent to fracture risk among controls exposed to pain treatment.

Elevated risk of clinical fractures and associated risk factors in patients with systemic lupus erythematosus versus matched controls: a population-based study in the United Kingdom.

UNLABELLED: The incidence of clinical fractures and the associated factors were assessed in patients with systemic lupus erythematosus (SLE) versus matched controls. We found an increased fracture risk in SLE patients compared to controls. Glucocorticoid use, longer disease duration, neuropsychiatric disease complications and previous osteoporotic fractures were identified as associated factors. INTRODUCTION: The aims of this study were to estimate the risk of clinical fractures in patients with SLE versus matched controls and to evaluate the risk factors associated with clinical fractures in SLE. METHODS: This is a population-based cohort study using the Clinical Practice Research Datalink (from 1987-2012). Each SLE patient (n = 4,343) was matched with up to six controls (n = 21,780) by age and sex. Clinical fracture type was stratified according to the WHO definitions into osteoporotic and non-osteoporotic fracture. Cox proportional hazards calculated relative rates (RR) of clinical fracture and time interaction terms to evaluate the timing patterns of fracture. Clinical fracture rates in SLE patients, stratified by age, gender, type of fracture, disease duration and therapy variables, were compared with those rates in controls. RESULTS: Follow-up durations were 6.4 years in SLE patients and 6.6 years in controls. SLE patients had a 1.2-fold increased clinical fracture risk compared to controls (adjusted RR = 1.22, 95% CI = 1.05-1.42), and the risk further increased with a longer disease duration. Glucocorticoid (GC) use in the previous 6 months raised the risk of clinical fracture (adjusted RR = 1.27, 95% CI = 1.02-1.58). Cerebrovascular events, seizures and previous osteoporotic fractures were identified as predictors of clinical fractures. CONCLUSIONS: We found an increased risk of clinical fracture in SLE patients compared to controls. GC use in the previous 6 months and longer disease duration are associated with the increased fracture risk in SLE. Patients with neuropsychiatric organ damage or previous osteoporotic fractures are also at increased risk of the occurrence of clinical fractures.

The risk of major and any (non-hip) fragility fracture after hip fracture in the United Kingdom: 2000-2010.

UNLABELLED: The risk of a subsequent major or any fracture after a hip fracture and secular trends herein were examined. Within 1 year, 2.7 and 8.4% of patients sustained a major or any (non-hip) fracture, which increased to 14.7 and 32.5% after 5 years. Subsequent fracture rates increased during the study period both for major and any (non-hip) fracture. INTRODUCTION: Hip fractures are associated with subsequent fractures, particularly in the year following initial fracture. Age-adjusted hip fracture rates have stabilised in many developed countries, but secular trends in subsequent fracture remain poorly documented. We thus evaluated secular trends (2000-2010) and determinants for the risk of a subsequent major (humerus, vertebral, or forearm) and any (non-hip) fracture after hip fracture. METHODS: Patients ≥50 years with a hip fracture between 2000 and 2010 were extracted from the UK Clinical Practice Research Datalink (n = 30,516). Incidence rates, cumulative incidence probabilities, and adjusted hazard ratios (aHRs) were calculated. RESULTS: Within 1 year following hip fracture, 2.7 and 8.4% of patients sustained a major or any (non-hip) fracture, which increased to 14.7 and 32.5% after 5 years, respectively. The most important risk factors for a subsequent major fracture within 1 year were the female gender [aHR 1.90, 95% confidence interval (CI) 1.51-2.40] and a history of secondary osteoporosis (aHR 1.54, 95% CI 1.17-2.02). The annual risk increased during the study period for both subsequent major (2009-2010 vs. 2000-2002: aHR 1.44, 95% CI 1.12-1.83) and any (non-hip) facture (2009-2010 vs. 2000-2002: aHR 1.80, 95% CI 1.58-2.06). CONCLUSION: The risk of sustaining a major or any (non-hip) fracture after hip fracture is small in the first year. However, given the recent rise in secondary fracture rates and the substantial risk of subsequent fracture in the longer term, fracture prevention is clearly indicated for patients who have sustained a hip fracture.

Antidepressant prescribing in five European countries: application of common definitions to assess the prevalence, clinical observations, and methodological implications.

PURPOSE: Drug utilization studies have applied different methods to various data types to describe medication use, which hampers comparisons across populations. The aim of this study was to describe the time trends in antidepressant prescribing in the last decade and the variation in the prevalence, calculated in a uniform manner, in seven European electronic healthcare databases. METHODS: Annual prevalence per 10,000 person-years (PYs) was calculated for 2001-2009 in databases from Spain, Germany, Denmark, the United Kingdom (UK), and the Netherlands. Prevalence data were stratified according to age, sex, antidepressant type (selective serotonin re-uptake inhibitors [SSRIs] or tricyclic antidepressants [TCAs]) and major indications. RESULTS: The age- and sex-standardized prevalence was lowest in the two Dutch (391 and 429 users per 10,000 PYs) and highest in the two UK (913 and 936 users per 10,000 PYs) populations in 2008. The prevalence in the Danish, German, and Spanish populations was 637, 618, and 644 users per 10,000 PY respectively. Antidepressants were prescribed most often in 20- to 60-year-olds in the two UK populations compared with the others. SSRIs were prescribed more often than TCAs in all except the German population. In the majority of countries we observed an increasing trend of antidepressant prescribing over time. Two different methods identifying recorded indications yielded different ranges of proportions of patients recorded with the specific indication (15-57% and 39-69% for depression respectively). CONCLUSION: Despite applying uniform methods, variations in the prevalence of antidepressant prescribing were obvious in the different populations. Database characteristics and clinical factors may both explain these variations.

Glucose-lowering agents and the patterns of risk for cancer: a study with the General Practice Research Database and secondary care data.

INTRODUCTION: Recent studies suggesting an increased cancer risk with glucose-lowering agents have received widespread publicity. The objectives of this study were to evaluate the comparability in underlying cancer risk and patterns of cancer risk over time with different glucose-lowering agents. METHODS: The General Practice Research Database (GPRD) was used to identify cohorts of new users. Cancer outcomes were obtained from the GPRD, Hospital Episode Statistics and cancer registries. Relative rates of cancer comparing different glucose-lowering agents were estimated using Poisson regression. RESULTS: A total of 206,940 patients was identified. There was no difference in cancer risk and quartile for HbA(1c) value. There were differences in cancer incidence in the first 6 months after starting treatment (adjusted relative rate of 0.83 [95% CI 0.70, 0.99] with thiazolidinediones, 1.34 [95% CI 1.19, 1.51] with sulfonylureas and 1.79 [95% CI 1.53, 2.10] with insulin, compared with metformin). Insulin users had decreasing cancer incidence over time (adjusted relative rate of 0.58 [95% CI 0.50, 0.68] during months 6-24, relative rate of 0.50 [95% CI 0.42, 0.59] during months 25-60 and relative rate of 0.48 [95% CI 0.40, 0.59] during months 60+) compared with months 0-6 after starting insulin. Similar patterns were found with sulfonylureas and metformin. There were no increases over time with insulin glargine (A21Gly, B31Arg, B32Arg human insulin; relative rate of 0.70 [95% CI 0.52, 0.95], 0.77 [95% CI 0.56, 1.07] and 0.60 [95% CI 0.36, 1.02], respectively, for 6-24, 25-60 and >60 months). CONCLUSIONS: These findings do not provide evidence of either beneficial or adverse effects of glucose-lowering agents on cancer risk and are consistent with changes in diabetes treatment in the few months prior to the diagnosis of cancer.

Causes of death in patients with multiple sclerosis and matched referent subjects: a population-based cohort study.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) has been associated with increased mortality rates. However, influence of lifestyle parameters remains unknown, and inconsistencies exist regarding findings for causes of death. METHODS: We conducted a population-based cohort study using the General Practice Research Database, Hospital Episode Statistics, and national death certificates (January 2001 through March 2008). To each patient with MS (n = 1270), up to six referent subjects without MS were matched by age, gender, and practice. Cox proportional hazards models were used to estimate mortality rate ratios (HRs). RESULTS: Patients with MS had a 3.5-fold increased mortality rate for all-cause mortality, compared with referent subjects (HR 3.51, 95% CI 2.63-4.69). The rate further increased amongst current smokers (HR 6.72, 95% CI 4.16-10.87) (but not in ex-smokers) and subjects with a body mass index of <20 kg/m(2) (HR 6.67, 95% CI 3.50-12.73). The HR was highest for infectious/respiratory-related deaths (HR 7.69, 95% CI 4.92-12.02) and was significantly increased for deaths related to cardiovascular diseases (2.4-fold) and cancer (1.9-fold), but not for accidents and suicide related deaths. CONCLUSION: British patients with MS have a 3.5-fold increased mortality rate compared with the general population. Smoking and respiratory diseases are major (potentially preventable) factors related to increased mortality rate amongst patients with MS.

Dopaminergic drugs and the risk of hip or femur fracture: a population-based case-control study.

SUMMARY: The effect of dopaminergic medication on the risk of hip/femur fractures is not clear. Our results showed a nearly twofold increased risk of hip/femur fractures in current dopaminergic drug users. Concomitant use of antidepressants further increased this risk. Fracture risk assessment may be warranted in elderly users of dopaminergic drugs. INTRODUCTION: Dopaminergic drugs, often used in the treatment of Parkinson's disease, have several pharmacological effects that may increase or decrease the risk of falling and fractures. Thus, the effect of dopaminergic medication on the risk of hip/femur fractures is not clear. The objective of the study was to examine the effect of dopaminergic medication and concomitant use of psychotropics on the risk of hip/femur fractures taking into account the timing of dopaminergic drug use. METHODS: A population-based case-control study in the PHARMO database was conducted for the period 1991 to 2002. Cases were patients aged 18 years and older with a first hip or femur fracture and matched to four control patients by year of birth, sex and geographical region. RESULTS: The study population included 6,763 cases and 26,341 controls. Current use of dopaminergic drugs (1-30 days before the index date) was associated with an increased risk of hip/femur fractures compared to never use (OR(adj) 1.76, 95% CI = 1.39-2.22), but this excess risk rapidly dropped to baseline levels when treatment had been discontinued >1 year ago. Concomitant use of antidepressants among current dopaminergic drug users further increased the risk of hip/femur fractures (OR(adj) 3.51, 95% CI = 2.10-5.87) while there was no additional risk with concomitant use of other psychotropics. CONCLUSIONS: Although the observed association between dopaminergic drugs and fracture risk may not be entirely causal, due to absence of information on the (severity of the) underlying disease, fracture risk assessment may be warranted in elderly users of dopaminergic drugs.

Long-acting {beta}2-agonists in adult asthma and the pattern of risk of death and severe asthma outcomes: a study using the GPRD.

The objective of this study was to describe risks of death and asthma outcomes with prescription of long-acting ß(2)-agonists (LABA), short-acting ß(2)-agonists (SABA) or inhaled corticosteroids (ICS) in general practice. The study population included ß(2)-agonist users aged ≥18 yrs, who were in the UK General Practice Research Database (GPRD), which is linked to the national registry of hospitalisations. The study included 507,966 patients with 5.5 million SABA, 4.0 million ICS and 1.3 million LABA prescriptions. Rates of asthma outcome increased with more severe treatment steps. The mortality rate was increased with least and most severe treatment steps. Higher relative rates (RR) of outcomes were found in recent starters and heavy long-term users with LABA, SABA and ICS. The RRs in heavy long-term users were 1.9 for all-cause mortality and 3.0 for asthma death with SABA, 1.4 and 1.6, respectively, with LABA and 1.7 and 2.2, respectively, with ICS. The RR of death was statistically similar over time between LABA and ICS despite changes in exposure. Risks for death and asthma outcomes varied substantially with exposure characteristics. The statistical power for detecting increases in asthma death was low. The results of this study did not indicate that LABA exposure was associated with an increased risk for all-cause mortality.

Ankylosing spondylitis and the risk of fracture: results from a large primary care-based nested case-control study.

BACKGROUND AND AIMS: Ankylosing spondylitis (AS) is associated with bone loss in the vertebrae and an increased prevalence of vertebral fractures, but literature about the magnitude of the risk of fracturing is limited. One retrospective cohort study provided evidence of an increased risk of clinical vertebral fractures but not of non-vertebral fractures. This study further explores the risk of clinical vertebral and non-vertebral fractures in a large population database. METHODS: In a primary care-based nested case-control study, 231,778 patients with fracture and 231,778 age- and sex-matched controls were recruited. A history of AS was assessed from the medical records. Odds ratios (OR) and 95% confidence intervals (CI) were calculated after adjustment for medication, other illnesses, smoking and body mass index when known. RESULTS: AS was diagnosed in 758 subjects. The prevalence of AS was 0.18% in patients with fracture and 0.15% in controls. Patients with AS had an increased risk of clinical vertebral fracture (OR 3.26; 95% CI 1.51 to 7.02). The risk of fractures of the forearm and hip was not significantly increased (OR 1.21; 95% CI 0.87 to 1.69 and OR 0.77; 95% CI 0.43 to 1.37, respectively). The risk of any clinical fracture was increased in patients with AS with a history of inflammatory bowel disease (OR 2.79; 95% CI 1.10 to 7.08), whereas it was decreased in patients with AS taking non-steroidal anti-inflammatory drugs (OR 0.65; 95% CI 0.50 to 0.84). The risk was not associated with recent back pain, psoriasis, joint replacement therapy and use of sulfasalazine. CONCLUSIONS: Patients with AS have an increased risk of clinical vertebral fracture but not of non-vertebral fractures, while the risk of any clinical fracture is increased in patients with concomitant inflammatory bowel disease. The mechanism by which non-steroidal anti-inflammatory drugs reduce the risk of any clinical fracture warrants further research.