Hubert G. M. Leufkens

Use of Oral Corticosteroids and Risk of Fractures

Treatment with systemic corticosteroids is known to increase the risk of fractures but little is known of the fracture risks associated with inhaled corticosteroids. A retrospective cohort study was conducted using a large UK primary care database (the General Practice Research Database [GPRD]). Inhaled corticosteroid users aged 18 years or older were compared with matched control patients and to a group of noncorticosteroid bronchodilator users. Patients with concomitant use of systemic corticosteroids were excluded. The study comprised 170,818 inhaled corticosteroid users, 108,786 bronchodilator users, and 170,818 control patients. The average age was 45.1 years in the inhaled corticosteroid, 49.3 years in the bronchodilator, and 45.2 years in the control groups. In the inhaled corticosteroid cohort, 54.5% were female. The relative rates (RRs) of nonvertebral, hip, and vertebral fractures during inhaled corticosteroid treatment compared with control were 1.15 (95% CI, 1.10–1.20), 1.22 (95% CI, 1.04–1.43), and 1.51 (95% CI, 1.22–1.85), respectively. No differences were found between the inhaled corticosteroid and bronchodilator groups (nonvertebral fracture RR = 1.00; 95% CI, 0.94–1.06). The rates of nonvertebral fractures among users of budesonide (RR = 0.95; 95% CI, 0.85–1.07) and fluticasone propionate (RR = 1.03; 95% CI, 0.71–1.49) were similar to the rate determined for users of beclomethasone dipropionate. We conclude that users of inhaled corticosteroids have an increased risk of fracture, particularly at the hip and spine. However, this excess risk may be related more to the underlying respiratory disease than to inhaled corticosteroid.

The Epidemiology of Corticosteroid-Induced Osteoporosis: a Meta-analysis

Abstract: Studies of oral corticosteroid dose and loss of bone mineral density have reported inconsistent results. In this meta-analysis, we used information from 66 papers on bone density and 23 papers on fractures to examine the effects of oral corticosteroids on bone mineral density and risk of fracture. Strong correlations were found between cumulative dose and loss of bone mineral density and between daily dose and risk of fracture. The risk of fracture was found to increase rapidly after the start of oral corticosteroid therapy (within 3 to 6 months) and decrease after stopping therapy. The risk remained independent of underlying disease, age and gender. We conclude that oral corticosteroid treatment using more than 5 mg (of prednisolone or equivalent) daily leads to a reduction in bone mineral density and a rapid increase in the risk of fracture during the treatment period. Early use of preventive measures against corticosteroid-induced osteoporosis is recommended.

Epidemiology of fractures in England and Wales.

Records from the General Practice Research Database were used to derive age- and gender-specific fracture incidence rates for England and Wales during the period 1988-1998. In total, 103,052 men and 119,317 women in the sample of 5 million adults sustained a fracture over 10.4 million and 11.2 million person-years (py) of follow-up. Among women, the most frequent fracture sites were the radius/ulna (30.2 cases per 10,000 py) and femur/hip (17.0 per 10,000 py). In men, the most common fracture was that of the carpal bones (26.2 per 10,000 py); the incidence of femur/hip fracture was 5.3 per 10,000 py. Varying patterns of fracture incidence were observed with increasing age; whereas some fractures became more common in later life (vertebral, distal forearm, hip, proximal humerus, rib, clavicle, pelvis), others were more frequent in childhood and young adulthood (tibia, fibula, carpus, foot, ankle). The lifetime risk of any fracture was 53.2% at age 50 years among women, and 20.7% at the same age among men. Whereas fractures of the proximal femur and vertebral body were associated with excess mortality over a 5 year period following fracture diagnosis among both men and women, fractures of the distal forearm were associated with only slight excess mortality in men. This study provides robust estimates of fracture incidence that will assist health-care planning and delivery.

Adverse drug events in hospitalized patients A comparison of doctors, nurses and patients as sources of reports

AbstractObjective: This study investigated the relative value of adverse drug events reported by doctors, nurses and patients. Methods: The study was conducted on a total of four wards: the paediatric and internal medicine wards (including geriatric patients) of two peripheral hospitals in the Netherlands. Adverse drug events were collected by spontaneous reporting (doctor and nurse reports) and by daily ward visits, during which the patients were interviewed by a hospital pharmacist (patient reports). Criteria for relative value of the reported adverse drug events were the number of potentially serious reactions, the number of reactions not mentioned in the patient information leaflet and the number of reactions reported to new drugs (5 years or less on the Dutch market). No formal causality assessment was applied. Results: Over a period of 2 months in 1996 (Hospital I) and 2 months in 1997 (Hospital II) a total of 620 patients were included in the study and adverse drug events were reported in 179 (29%) of these cases. Doctors reported a statistically significant larger number of serious (26% of all doctor reports; odds ratio (OR) 3.2; confidence interval (CI) 1.2–8.7) and unknown (39%; OR 2.5; CI 1.0–6.0) adverse drug events than patients themselves during the daily ward visit. Doctors also reported more serious and unknown adverse drug events than nurses. Adverse reactions to new drugs were reported during the daily ward visit only (8% of all daily ward visit reports). Conclusion: This study reconfirms that doctors are the main source for reports of serious and unknown adverse drug events in hospitalized patients. However, patients themselves seem to report more adverse reactions to new drugs (during the daily ward visit). By focusing on patients using new drugs, the daily ward visit might become cost-effective. This needs to be explored in future studies.

Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case–control study

Objective: To assess whether use of oral glucocorticoids is associated with cardiovascular and cerebrovascular morbidity. Design and setting: Nested case–control study within a cohort of patients (⩾ 50 years old) with at least one prescription for oral or non-systemic glucocorticoids. Data were from the general practice research database. Patients: 50 656 patients were identified with a first record for ischaemic heart disease (International classification of diseases, ninth revision (ICD-9) codes 410, 411, 413, and 414), ischaemic stroke or transient ischaemic attack (ICD-9 codes 430–436), or heart failure (ICD-9 code 428) between 1988 and 1998. One control was matched to each case by sex, age, general practice, underlying disease, and calendar time. Main outcome measure: Odds ratio (OR) of cardiovascular or cerebrovascular events in patients using oral glucocorticoids compared with non-users. Results: There was a significant association between ever use of oral glucocorticoids and any cardiovascular or cerebrovascular outcome (adjusted OR 1.25, 95% confidence interval (CI) 1.21 to 1.29). The association was stronger for current use of oral glucocorticoids than for recent or past use. Among current users, the highest ORs were observed in the group with the highest average daily dose, although the dose–response relation was not continuous. Current use was associated with an increased risk of heart failure (adjusted OR 2.66, 95% CI 2.46 to 2.87), which was consistent between patients with rheumatoid arthritis, patients with chronic obstructive pulmonary disease, and patients without either of the two conditions. Also, current use was associated with a smaller increased risk of ischaemic heart disease (OR 1.20, 95% CI 1.11 to 1.29). Conclusions: Oral glucocorticoid use was identified as a risk factor for heart failure. However, the evidence remains observational and only a randomised controlled trial of glucocorticoid treatment versus other disease modifying agents is likely to distinguish the importance of the underlying disease activity from its treatment in predicting cardiovascular outcomes.

Psychoactive substance use and the risk of motor vehicle accidents

The driving performance is easily impaired as a consequence of the use of alcohol and/or licit and illicit drugs. However, the role of drugs other than alcohol in motor vehicle accidents has not been well established. The objective of this study was to estimate the association between psychoactive drug use and motor vehicle accidents requiring hospitalisation. A prospective observational case-control study was conducted in the Tilburg region of The Netherlands from May 2000 to August 2001. Cases were car or van drivers involved in road crashes needing hospitalisation. Demographic and trauma related data was collected from hospital and ambulance records. Urine and/or blood samples were collected on admission. Controls were drivers recruited at random while driving on public roads. Sampling was conducted by researchers, in close collaboration with the Tilburg police, covering different days of the week and times of the day. Respondents were interviewed and asked for a urine sample. If no urine sample could be collected, a blood sample was requested. All blood and urine samples were tested for alcohol and a number of licit and illicit drugs. The main outcome measures were odds ratios (OR) for injury crash associated with single or multiple use of several drugs by drivers. The risk for road trauma was increased for single use of benzodiazepines (adjusted OR 5.1 (95% Cl: 1.8-14.0)) and alcohol (blood alcohol concentrations of 0.50-0.79 g/l, adjusted OR 5.5 (95% Cl: 1.3-23.2) and >or=0.8 g/l, adjusted OR 15.5 (95% Cl: 7.1-33.9)). High relative risks were estimated for drivers using combinations of drugs (adjusted OR 6.1 (95% Cl: 2.6-14.1)) and those using a combination of drugs and alcohol (OR 112.2 (95% Cl: 14.1-892)). Increased risks, although not statistically significantly, were assessed for drivers using amphetamines, cocaine, or opiates. No increased risk for road trauma was found for drivers exposed to cannabis. The study concludes that drug use, especially alcohol, benzodiazepines and multiple drug use and drug-alcohol combinations, among vehicle drivers increases the risk for a road trauma accident requiring hospitalisation.

Incidence and natural history of Paget's disease of bone in England and Wales.

This study used a large, primary care, record‐linkage resource (the General Practice Research Database [GPRD]) to evaluate the incidence, clinical presentation, and natural history of Pagets disease of bone in England and Wales. Between 1988 and 1999, we identified 2465 patients with the recorded diagnosis of Pagets disease of bone, within the five million subjects ≥18 years old who were registered in the GPRD. The validity of diagnostic recording was assessed by questionnaire to individual general practitioners (GPs) in 150 patients; the diagnosis was confirmed in 93.8% of responders. The mean age of patients with Pagets disease was 75 years and 51% were men. The prevalence of the disorder was 0.3% among men and women aged ≥55 years; incidence rates for clinically diagnosed Pagets disease rose steeply with age (men, 5 per 10,000 person‐years; women, 3 per 10,000 person‐years at the age of 75 years). Over the 11‐year period of the study, the age‐ and sex‐adjusted incidence rate of clinically diagnosed Pagets disease declined from 1.1 per 10,000 person‐years to 0.7 per 10,000 person‐years. Each patient with Pagets disease was matched to three controls matched by age, gender, and general practice. Cases had a greater risk of back pain (relative risk [RR], 2.1; 95% CI, 1.9‐2.3), osteoarthritis (OA; RR, 1.7; 95% CI, 1.5‐1.9), hip arthroplasty (RR, 3.1; 95% CI, 2.4‐4.1), knee arthroplasty (RR, 1.6; 95% CI, 1.0‐2.6), fracture (RR, 1.2; 95% CI, 1.0‐1.5), and hearing loss (RR, 1.6; 95% CI, 1.3‐1.9). Seven patients with Pagets disease developed a malignant bone neoplasm (0.3%). Using life table methodology, the estimated number of people who died within 5 years of follow‐up was 32.7% among the patients with Pagets disease and 28.0% among the control patients.

Does a Fracture at One Site Predict Later Fractures at Other Sites? A British Cohort Study

Abstract: The extent to which a fracture at one skeletal site predicts further fractures at other sites remains uncertain. We addressed this issue using information from the UK General Practice Research Database, which contains the medical records of general practitioners; our study population consisted of all patients aged 20 years or older with an incident fracture during 1988 to 1998. We identified 222 369 subjects (119 317 women, 103 052 men) who had sustained at least one fracture during follow-up. There was a 2- to 3-fold increase in the risk of subsequent fractures at different skeletal sites. A patient with a radius/ulna fracture had a standardized incidence ratio (SIR) of 3.0 (95% confidence interval 2.9–3.1) for fractures at a different skeletal site; for initial vertebral fracture, this ratio was 2.9 (2.8–3.1) and for initial femur/hip fracture it was 2.6 (2.5–2.7). The SIRs were generally higher among men than women. Men aged 65–74 years with a radius/ulna fracture or vertebral fracture had substantially higher rates of subsequent femur/hip fractures than expected; SIRs were 6.0 (3.4–9.9) and 13.4 (7.3–22.5). Corresponding SIRs among women of similar age were 3.3 (2.8–3.9) and 5.8 (4.1–8.1), respectively. Men and women aged 65 years or older with a vertebral fracture had a 5-year risk of femur/hip fracture of 6.7% and 13.3%, respectively. Our results indicate that fractures at any site are strong risk factors for subsequent fractures, among both elderly men and women.

5-Aminosalicylate use and colorectal cancer risk in inflammatory bowel disease: a large epidemiological study.

Background and aims: The objective of this study was to evaluate the risk of colorectal cancer (CRC) in patients taking aminosalicylates (5-ASA) for inflammatory bowel disease (IBD). Methods: The General Practice Research Database (GPRD) which contains the primary care records of five million people in the UK was used to identify users of mesalazine, balsalazide, olsalazine, or sulfasalazine with a history of IBD. In a nested case control analysis, each incident CRC case with any use of a 5-ASA in the six months before the CRC diagnosis was matched by age, sex, and calendar time to six control patients who were also currently using a 5-ASA. Patients were then classified according to regularity of use. The analysis was controlled for body mass index, IBD duration, history of colorectal polyps, use of non-steroidal anti-inflammatory drugs, paracetamol, aspirin, immunosuppressants, oral and rectal glucocorticoids, prior gastrointestinal hospitalisation, recorded colonoscopy, and number of visits to the general practitioner for IBD symptoms in the 6–24 months before diagnosis. Results: The study population included 18 969 patients, of whom 100 had developed CRC during 5-ASA exposure. Most of these cases had a history of ulcerative colitis (76 patients). In the case control analysis, regular users, defined as having six or more 5-ASA prescriptions in the previous 12 months, were found to have a decreased risk of CRC compared with irregular users (crude odds ratio (OR) 0.7 (0.44–1.03); adjusted OR 0.60 (0.38–0.96)). Regular users of sulfasalazine with 6–12 prescriptions before had an adjusted OR of 0.95 (0.22–4.11); with 13–30 prior prescriptions this was 0.41 (0.14–1.20) and with >30 prior prescriptions this was 0.77 (0.37–1.60). For mesalazine users, these values were 1.13 (0.49–2.59), 0.30 (0.11–0.83), and 0.31 (0.11–0.84), respectively. Conclusion: These results show that regular 5-ASA use is associated with some reduction in the risk of CRC developing in ulcerative colitis.

Safety-Related Regulatory Actions for Biologicals Approved in the United States and the European Union

CONTEXT Biologicals are a relatively new class of medicines that carry specific risks (eg, immunogenicity). However, limited information is available on the nature and timing of safety problems with their use that were identified after approval. OBJECTIVE To determine the nature, frequency, and timing of safety-related regulatory actions for biologicals following approval in the United States and/or the European Union. DESIGN AND SETTING Follow-up of a group of biologicals approved in the United States and/or European Union between January 1995 and June 2007. Vaccines, allergenic products, and products for further manufacture and transfusion purposes were excluded. MAIN OUTCOME MEASURES Nature, frequency, and timing of safety-related regulatory actions defined as (1) dear healthcare professional letters (United States) and direct healthcare professional communications (European Union), (2) black box warnings (United States), and (3) safety-related marketing withdrawals (United States and European Union) issued between January 1995 and June 2008. RESULTS A total of 174 biologicals were approved (136 in the United States and 105 in the European Union, of which 67 were approved in both regions). Eighty-two safety-related regulatory actions (46 dear healthcare professional letters, 17 direct healthcare professional communications, 19 black box warnings, and no withdrawals) were issued for 41 of the 174 different biologicals (23.6%). The probability of a first safety-related regulatory action, derived from Kaplan-Meier analyses, was 14% (95% confidence interval [CI], 9%-19%) 3 years after approval and 29% (95% CI, 20%-37%) 10 years after approval. Biologicals first in class to obtain approval had a higher risk for a first safety-related regulatory action compared with later approved products in that class (12.0/1000 vs 2.9/1000 months, respectively; hazard ratio, 3.7 [95% CI, 1.5-9.5]). Warnings mostly concerned the classes general disorders and administration site conditions, infections and infestations, immune system disorders and neoplasms benign, malignant, and unspecified. CONCLUSIONS The nature of safety problems identified after approval for biologicals is often related to the immunomodulatory effect (infections). Because the biologicals first to be approved in a class were more likely to be subjected to regulatory action, close monitoring is recommended.