T P van Staa

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.

Excess mortality following hip fracture: a systematic epidemiological review.

Summary This systematic literature review has shown that patients experiencing hip fracture after low-impact trauma are at considerable excess risk for death compared with nonhip fracture/community control populations. The increased mortality risk may persist for several years thereafter, highlighting the need for interventions to reduce this risk.Patients experiencing hip fracture after low-impact trauma are at considerable risk for subsequent osteoporotic fractures and premature death. We conducted a systematic review of the literature to identify all studies that reported unadjusted and excess mortality rates for hip fracture. Although a lack of consistent study design precluded any formal meta-analysis or pooled analysis of the data, we have shown that hip fracture is associated with excess mortality (over and above mortality rates in nonhip fracture/community control populations) during the first year after fracture ranging from 8.4% to 36%. In the identified studies, individuals experienced an increased relative risk for mortality following hip fracture that was at least double that for the age-matched control population, became less pronounced with advancing age, was higher among men than women regardless of age, was highest in the days and weeks following the index fracture, and remained elevated for months and perhaps even years following the index fracture. These observations show that patients are at increased risk for premature death for many years after a fragility-related hip fracture and highlight the need to identify those patients who are candidates for interventions to reduce their risk.

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.

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.

A comparison of risk stratification schemes for stroke in 79,884 atrial fibrillation patients in general practice.

Summary.  Background:  Anticoagulation management of patients with atrial fibrillation (AF) should be tailored individually on the basis of ischemic stroke risk. The objective of this study was to compare the predictive ability of 15 published stratification schemes for stroke risk in actual clinical practice in the UK. Methods:  AF patients aged ≥ 18 years in the General Practice Research Database, which contains computerized medical records, were included. The c‐statistic was estimated to determine the predictive ability for stroke for each scheme. Outcomes included stroke, hospitalizations for stroke, and death resulting from stroke (as recorded on death certificates). Results:  The study cohort included 79 844 AF patients followed for an average of 4 years (average of 2.4 years up to the start of warfarin therapy). All risk schemes had modest discriminatory ability in AF patients, with c‐statistics for predicting events ranging from 0.55 to 0.69 for strokes recorded by the general practitioner or in hospital, from 0.56 to 0.69 for stroke hospitalizations, and from 0.56 to 0.78 for death resulting from stroke as reported on death certificates. The proportion of patients assigned to individual risk categories varied widely across the schemes, with the proportion categorized as moderate risk ranging from 12.7% (CHA2DS2‐VASc) to 61.5% (modified CHADS2). Low‐risk subjects were truly low risk (with annual stroke events < 0.5%) with the modified CHADS2, National Institute for Health and Clinical Excellence and CHA2DS2‐VASc schemes. Conclusion:  Current published risk schemes have modest predictive value for stroke. A new scheme (CHA2DS2‐VASc) may discriminate those at truly low risk and minimize classification of subjects as intermediate/moderate risk. This approach would simplify our approach to stroke risk stratification and improve decision‐making for thromboprophylaxis in patients with AF.

Initiation and persistence of warfarin or aspirin in patients with chronic atrial fibrillation in general practice: do the appropriate patients receive stroke prophylaxis?

Summary.  Background: Practice guidelines recommend long‐term stroke prophylaxis in patients with chronic atrial fibrillation (cAF). Objectives: To examine treatment initiation and persistence and factors that influence the choice of cAF treatment. Patients/methods: This study used the General Practice Research Database, including computerized medical records of general practitioners in the UK. Patients aged 40+ years with cAF after 1 January 2000 were included. Cox proportional hazards regression models evaluated initiation and treatment continuation over time of warfarin and aspirin. Treatment discontinuation was defined as no repeat prescription within a three‐month period after the expected end of the treatment course. Results: The study population included 41 910 cAF patients. Elderly patients (aged 85+) were less likely to start warfarin [relative rate (RR) = 0.16, 95% confidence interval (CI) 0.15–0.18] and more likely to start aspirin (RR = 1.66, 95% CI 1.47–1.88) than patients aged 40–64 years. A history of dementia (RR = 0.28, 95% CI 0.17–0.44) and falls (RR = 0.76, 95% CI 0.70–0.83) also reduced the likelihood of warfarin initiation. Adjusting for age and gender, higher stroke risk (CHADS2 score) was not found to be associated with initiation of warfarin or aspirin contrary to current guidelines recommendations. One‐year persistence was 70% for warfarin and 50% for aspirin. Treatment persistence was higher in elderly patients using warfarin and aspirin. A higher CHADS2 score was associated with improved persistence only with warfarin. Conclusions: The low likelihood of patients with cAF in general practice remaining on treatment long‐term indicates that not all benefits as observed in clinical trials may be achieved in usual clinical practice.