Colleen Metge

Use of proton pump inhibitors and risk of osteoporosis-related fractures.

Background: The use of proton pump inhibitors has been associated with an increased risk of hip fracture. We sought to further explore the relation between duration of exposure to proton pump inhibitors and osteoporosis-related fractures. Methods: We used administrative claims data to identify patients with a fracture of the hip, vertebra or wrist between April 1996 and March 2004. Cases were each matched with 3 controls based on age, sex and comorbidities. We calculated adjusted odds ratios (OR) for the risk of hip fracture and all osteoporosis-related fractures for durations of proton pump inhibitor exposure ranging from 1 or more years to more than 7 years. Results: We matched 15 792 cases of osteoporosis-related fractures with 47 289 controls. We did not detect a significant association between the overall risk of an osteoportic fracture and the use of proton pump inhibitors for durations of 6 years or less. However, exposure of 7 or more years was associated with increased risk of an osteoporosis-related fracture (adjusted OR 1.92, 95% confidence interval [CI] 1.16–3.18, p = 0.011). We also found an increased risk of hip fracture after 5 or more years of exposure (adjusted OR 1.62, 95% CI 1.02–2.58, p = 0.04), with even higher risk after 7 or more years exposure (adjusted OR 4.55, 95% CI 1.68–12.29, p = 0.002). Interpretation: Use of proton pump inhibitors for 7 or more years is associated with a significantly increased risk of an osteoporosis-related fracture. There is an increased risk of hip fracture after 5 or more years exposure. Further study is required to determine the clinical importance of this finding and to determine the value of osteoprotective medications for patients with long-term use of proton pump inhibitors.

Validity of a prescription claims database to estimate medication adherence in older persons.

Background:Prescription claims data have been used to estimate refill medication adherence through calculations of cumulative medication acquisition (CMA) and cumulative medication gap (CMG) values. Few studies have assessed the validity of these calculated rates. Objectives:We sought to assess the validity of CMA and CMG calculated from the Manitoba prescription claims database (DPIN) against pill count medication adherence, targeting overall medications and angiotensin converting enzyme inhibitors (ACEIs). Methods:Using a survey of a convenience sample of subjects recruited through community pharmacies, subjects who were eligible for study (ie, 65 years or older, noninstitutionalized, taking 2 or more “discrete” prescribed medications, including an ACEI, and willing to provide informed consent) were studied. Pill counts were conducted on all prescribed medicines during 3 home interviews over the course of 4 months. Ten months of DPIN data also were collected on each subject. Results:The concordance between CMA and pill count for overall medications was 411/522 (79%) and for ACEIs was 89/101 (88%) with no systematic differences (McNemars P = 0.68 and P = 0.097, respectively). CMG and pill count showed even better concordance of 438/514 (85%) for overall medications and 96/101 (95%) for ACEIs, although systematic differences were noted for overall medications (McNemars P = 0.0012) but not for ACEIs (McNemars P = 0.500). Spearmans rank correlations were weak for all comparisons. Conclusions:The high concordance between prescription claims database and pill counts suggested that the rate with which patients refill their medications usually is consistent with the rate they consume them. DPIN is not accurate for nondiscrete dosage forms or medications prescribed for “as-required” use.

Fracture risk from psychotropic medications: a population-based analysis.

Background: Selective serotonin reuptake inhibitors (SSRIs), benzodiazepines, and antipsychotics have each been associated with an increased risk of fracture in older individuals. The aim of this study was to better define the magnitude of fracture risk with psychotropic medications and to determine whether a dose-effect relationship exists. Methods: Population-based administrative databases were used to examine psychotropic medication exposure and fractures in persons aged 50 years and older in Manitoba between 1996 and 2004. Persons with osteoporotic fractures (vertebral, wrist, or hip [n = 15,792]) were compared with controls (3 controls for each case matched for age, sex, ethnicity, and comordibity [n = 47,289]). Medications examined included antidepressants (SSRIs vs other monoamines), antipsychotics, lithium, and benzodiazepines. Results: Selective serotonin reuptake inhibitors were associated with the highest adjusted odds of osteoporotic fractures (odds ratio [OR] = 1.45; 95% confidence interval [CI], 1.32-1.59). Other monoamine antidepressants (OR = 1.15; 95% CI, 1.07-1.24) and benzodiazepines (OR = 1.10; 95% CI, 1.04-1.16) were also associated with greater fracture risk, although the relationship was weaker. Lithium was associated with lower fracture risk (OR = 0.63; 95% CI, 0.43-0.93), whereas the relationship with antipsychotics was not significant in the models that adjusted for diagnoses. A dose-effect relationship was seen with SSRIs and benzodiazepines. Conclusions: This study provides novel insight into the relationship between fractures and psychotropic medications in the elderly. Selective serotonin reuptake inhibitors seem to have a greater risk than other psychotropic classes, and higher doses may further increase that risk. Lithium seems to be protective against fractures.

The Relative Efficacies of Gastroprotective Strategies in Chronic Users of Nonsteroidal Anti-inflammatory Drugs

BACKGROUND & AIMS There are numerous gastroprotective strategies recommended for reducing the risk of upper gastrointestinal (GI) complications in long-term users of nonsteroidal anti-inflammatory drugs (NSAIDs). The relative efficacy of the different strategies alone or in combination is uncertain. METHODS We used the Manitoba Population Health Research Data Repository to perform a population-based matched case-control analysis. All NSAID users (nonselective and cyclooxygenase [COX]-2-specific) users admitted to the hospital with a primary diagnosis for an upper gastrointestinal complication were matched to NSAID-using controls in the community. We used conditional logistic regression analysis to determine the relative efficacy of different gastroprotective strategies (proton pump inhibitors [PPIs], COX-2 inhibitors, and low-dose/high-dose misoprostol) either alone or in combination and to adjust for multiple pertinent covariates. RESULTS A total of 1382 NSAID/COX-2 users with upper GI complications were matched to 33,957 age- and sex-matched controls. Cotherapy with PPIs or misoprostol or use of a COX-2 inhibitor all significantly reduced the risk of upper GI complications. COX-2 inhibitors were not statistically more likely to prevent upper GI complications than PPIs, although they were superior to low-dose misoprostol. The combination of COX-2 inhibitors with a PPI was associated with the greatest degree of upper GI complication risk reduction. CONCLUSIONS All of the commonly accepted gastroprotective strategies reduce the risk of upper GI complications in NSAID users, although the combination of COX-2 inhibitors with PPIs promotes the greatest risk reduction for NSAID-related upper GI complications. Celecoxib use specifically may be superior to the combination of nonselective NSAIDs with a PPI.

Establishing a Regional Bone Density Program: Lessons From the Manitoba Experience

In 1997, the province of Manitoba, Canada developed a regional bone density program to address concerns related to access, waiting times, and quality assurance. We report our experience with this model of bone density service delivery, which is unique in North America, and confront the challenge of balancing accessibility, clear guidelines, and fiscal responsibility.

Selective serotonin reuptake inhibitors are associated with a modest increase in the risk of upper gastrointestinal bleeding.

OBJECTIVES:The use of the common antidepressant class of serotonin-specific reuptake inhibitors (SSRIs) is associated with an increased risk of upper gastrointestinal bleeding (UGIB). Proton pump inhibitors (PPIs) have been demonstrated to reduce the risk of gastrointestinal bleeding secondary to other risk factors, most notably non-steroidal anti-inflammatory drug (NSAID) use. The role for PPIs in chronic SSRI users without other risk factors remains uncharacterized.METHODS:We used the Manitoba Population Health Research Data Repository to perform a population-based matched case–control analysis. All patients admitted to the hospital with a primary diagnosis of UGIB were matched to non-bleeding controls. We used conditional regression analysis to determine the risk of UGIB associated with SSRI use, and the risk reduction associated with concomitant PPI use, both for users and non-users of NSAIDs.RESULTS:SSRI use was associated with a modest increase in the risk of UGIB (odds ratio (OR), 1.43; 95% confidence interval (CI), 1.09–1.89). The addition of an SSRI to NSAID therapy did not significantly increase the risk of UGIB (OR, 1.20; 95% CI, 0.78–1.92) over use of an NSAID alone. PPI cotherapy significantly reduced the risk of SSRI-related UGIB (OR, 0.39; 95% CI, 0.16–0.94).CONCLUSIONS:SSRI use is associated with a modestly increased risk of UGIB, which may be significantly reduced with PPI cotherapy. SSRI use is not a major risk factor for NSAID-related UGIB.

Osteoporosis-related fracture case definitions for population-based administrative data

BackgroundPopulation-based administrative data have been used to study osteoporosis-related fracture risk factors and outcomes, but there has been limited research about the validity of these data for ascertaining fracture cases. The objectives of this study were to: (a) compare fracture incidence estimates from administrative data with estimates from population-based clinically-validated data, and (b) test for differences in incidence estimates from multiple administrative data case definitions.MethodsThirty-five case definitions for incident fractures of the hip, wrist, humerus, and clinical vertebrae were constructed using diagnosis codes in hospital data and diagnosis and service codes in physician billing data from Manitoba, Canada. Clinically-validated fractures were identified from the Canadian Multicentre Osteoporosis Study (CaMos). Generalized linear models were used to test for differences in incidence estimates.ResultsFor hip fracture, sex-specific differences were observed in the magnitude of under- and over-ascertainment of administrative data case definitions when compared with CaMos data. The length of the fracture-free period to ascertain incident cases had a variable effect on over-ascertainment across fracture sites, as did the use of imaging, fixation, or repair service codes. Case definitions based on hospital data resulted in under-ascertainment of incident clinical vertebral fractures. There were no significant differences in trend estimates for wrist, humerus, and clinical vertebral case definitions.ConclusionsThe validity of administrative data for estimating fracture incidence depends on the site and features of the case definition.

Using multiple data features improved the validity of osteoporosis case ascertainment from administrative databases

OBJECTIVES The aim was to construct and validate algorithms for osteoporosis case ascertainment from administrative databases and to estimate the population prevalence of osteoporosis for these algorithms. STUDY DESIGN AND SETTING Artificial neural networks, classification trees, and logistic regression were applied to hospital, physician, and pharmacy data from Manitoba, Canada. Discriminative performance and calibration (i.e., error) were compared for algorithms defined from different sets of diagnosis, prescription drug, comorbidity, and demographic variables. Algorithms were validated against a regional bone mineral density testing program. RESULTS Discriminative performance and calibration were poorer and sensitivity was generally lower for algorithms based on diagnosis codes alone than for algorithms based on an expanded set of data features that included osteoporosis prescriptions and age. Validation measures were similar for neural networks and classification trees, but prevalence estimates were lower for the former model. CONCLUSION Multiple features of administrative data generally resulted in improved sensitivity of osteoporosis case-detection algorithm without loss of specificity. However, prevalence estimates using an expanded set of features were still slightly lower than estimates from a population-based study with primary data collection. The classification methods developed in this study can be extended to other chronic diseases for which there may be multiple markers in administrative data.

The Association Between Corticosteroid Use and Development of Fractures Among IBD Patients in a Population-Based Database

OBJECTIVE:Because the rate of fracture among patients with inflammatory bowel disease (IBD) is only slightly higher than that in the general population, it is important to define high-risk groups worthy of diagnostic evaluation or prophylactic interventions. Corticosteroid use has been considered in other diseases to be a risk for fracture, although not all studies in IBD are concordant on this point. We aimed to determine whether patients with IBD drawn from a population-based database who sustain fractures are more likely to have been using corticosteroids than a matched group of IBD patients who did not fracture.METHODS:We extracted from our population-based University of Manitoba Inflammatory Bowel Disease Epidemiology Database the number of patients with a new diagnosis of fracture between the years 1997–2000. From within our Inflammatory Bowel Disease Epidemiology Database, we extracted a control group of IBD patients who did not develop fractures matched to the case group who did by age, gender, diagnosis, year of diagnosis, and geographic area of residence. We linked our cohorts with Manitoba Healths Drug Program Information Network to study corticosteroid use within 2 yr before fracture diagnosis. The Drug Program Information Network is a population-based database, established in 1995, which records all prescription drugs.RESULTS:Fractures were identified in 13 patients with Crohns disease and in 28 patients with ulcerative colitis. The control group included 103 Crohns disease and 173 ulcerative colitis patients who did not fracture. In Crohns disease, for the group who fractured compared with the controls who did not fracture, corticosteroid use before fracture was evident in seven (54%) compared with 21 (22%) who did not fracture (χ2 = 4.45, df = 1, p = 0.035). In ulcerative colitis, for the group who fractured compared with the controls who did not fracture, corticosteroid use before fracture was evident in five (18%) compared with 37 (21%) who did not fracture (χ2 = 0.031, df = 1, p = 0.861). Fracture cases were more likely to be exposed to oral corticosteroids (OR = 1.75; 95% CI = 0.82–3.75), but this result is not significant. Regarding corticosteroid dosing among the 12 patients with IBD who fractured and used corticosteroids, the mean total days supply was 314 days ± 236 days compared with 258 days ± 278 days in those who did not fracture (p = 0.16). The prescribed daily dose among corticosteroid users was comparable for those who fractured versus those who did not fracture (18 mg/day vs 21 mg/day, p = 0.90).CONCLUSIONS:Patients who require corticosteroids in Crohns disease should be considered at risk for fracture. Further research is required to delineate after how much corticosteroid use are subjects at risk and/or after what duration of active disease.

Association of Antiepileptic Drugs With Nontraumatic Fractures: A Population-Based Analysis

OBJECTIVE To explore the relationship between antiepileptic drug (AED) use and nontraumatic fractures in those aged 50 years and older. DESIGN Retrospective matched cohort study. PARTICIPANTS A total of 15,792 persons, identified through the Population Health Research Data Repository from Manitoba, Canada, with nontraumatic fractures of the wrist, hip, and vertebra occurring between 1996 and 2004. Each patient was matched for age, sex, ethnicity, and comorbidity with up to 3 controls (n = 47,289). INTERVENTIONS Prior AED use (carbamazepine, clonazepam, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, primidone, topiramate, valproic acid, and vigabatrin) was determined from pharmacy data in the repository. Odds ratios (OR) for fracture from AED exposure were adjusted for sociodemographic and comorbidity factors known to affect fracture risk. RESULTS A significant increase in fracture risk was found for most of the AEDs being investigated (carbamazepine, clonazepam, gabapentin, phenobarbital, and phenytoin). The adjusted ORs ranged from 1.24 (95% confidence interval [CI], 1.05-1.47) for clonazepam to 1.91 (95% CI, 1.58-2.30) for phenytoin. The only AED not associated with increased fracture risk was valproic acid (adjusted OR, 1.10; 95% CI, 0.70-1.72). CONCLUSIONS Most AEDs were associated with an increased risk of nontraumatic fractures in individuals aged 50 years or older. Further studies are warranted to assess the risk of nontraumatic fractures with the newer AEDs and to determine the efficacy of osteoprotective medications in this population.