Laura E. Targownik

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.

Proton-Pump Inhibitor Use Is Not Associated With Osteoporosis or Accelerated Bone Mineral Density Loss

BACKGROUNDS & AIMS Recent studies have shown an association between proton-pump inhibitor use (PPI) and hip fracture. The mechanism by which PPI use promotes the development of hip fracture is uncharacterized. Therefore, we sought to determine whether PPI use is associated with osteoporosis or accelerated bone mineral density (BMD) loss. METHODS We used the Manitoba Bone Mineral Density Database to determine the relationship between chronic PPI use and osteoporosis on an initial assessment of BMD and on BMD loss between successive assessments of BMD. In the cross-sectional study, cases with osteoporosis at the hip or lumbar vertebrae (T-score < or =-2.5) were matched to 3 controls with normal BMD (T-score > or =-1.0). In the longitudinal analysis, the change in BMD among PPI users and nonusers between successive BMD assessments was assessed. Conditional logistic regression and multivariate linear regression were used to obtain estimates of the association between PPI use and osteoporosis and of the annualized change in BMD associated with PPI use. RESULTS PPI use was not associated with having osteoporosis at either the hip (OR, 0.84; 95% CI, 0.55-1.34) or the lumbar spine (OR, 0.79; 95% CI, 0.59-1.06) for PPI use >1500 doses over the previous 5 years. In the longitudinal study no significant decrease was observed in BMD at either site attributable to PPI use. CONCLUSIONS PPI use does not appear to be associated with either the presence of osteoporosis or accelerated BMD loss. The association between PPI use and hip fracture is probably related to factors independent of osteoporosis.

Clinical Practice Guidelines for the Medical Management of Nonhospitalized Ulcerative Colitis: The Toronto Consensus

BACKGROUND & AIMS The medical management of ulcerative colitis (UC) has improved through the development of new therapies and novel approaches that optimize existing drugs. Previous Canadian consensus guidelines addressed the management of severe UC in the hospitalized patient. We now present consensus guidelines for the treatment of ambulatory patients with mild to severe active UC. METHODS A systematic literature search identified studies on the management of UC. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a working group of specialists. RESULTS The participants concluded that the goal of therapy is complete remission, defined as both symptomatic and endoscopic remission without corticosteroid therapy. The consensus includes 34 statements focused on 5 main drug classes: 5-aminosalicylate (5-ASA), corticosteroids, immunosuppressants, anti-tumor necrosis factor (TNF) therapies, and other therapies. Oral and rectal 5-ASA are recommended first-line therapy for mild to moderate UC, with corticosteroid therapy for those who fail to achieve remission. Patients with moderate to severe UC should undergo a course of oral corticosteroid therapy, with transition to 5-ASA, thiopurine, anti-TNF (with or without thiopurine or methotrexate), or vedolizumab maintenance therapy in those who successfully achieve symptomatic remission. For patients with corticosteroid-resistant/dependent UC, anti-TNF or vedolizumab therapy is recommended. Timely assessments of response and remission are critical to ensuring optimal outcomes. CONCLUSIONS Optimal management of UC requires careful patient assessment, evidence-based use of existing therapies, and thorough assessment to define treatment success.

The Epidemiology of Colectomy in Ulcerative Colitis: Results From a Population-Based Cohort

OBJECTIVES:Previous studies have reported colectomy rates of over 50% in ulcerative colitis (UC), although changes in management may have influenced the rates of colectomy in the modern era. We sought to determine the incidence of colectomy in UC and identify risk factors associated with early colectomy (EC) and late colectomy (LC).METHODS:We used the University of Manitoba Inflammatory Bowel Disease Epidemiology Database, a population-based data set including UC patients with up to 25 years of post diagnosis follow-up. We tracked the occurrence of total colectomy in all patients with known UC, subdivided into EC (≤90 days from diagnosis date) and LC (>90 days from diagnosis). Survival curves were created and stratified by age, sex, era of diagnosis, and inpatient/hospital diagnosis. Cox proportional hazards modeling was used to determine which risk factors were predictive of either EC or LC.RESULTS:Among 3,752 patients with UC, 367 underwent colectomy. The 5-, 10- and 20-year actuarial risk of requiring colectomy was 7.5%, 10.4%, and 14.8%, respectively. Male sex (hazard ratio (HR): 63, 95% confidence interval (CI): 1.58–4.36) and being initially diagnosed during a hospitalization (HR: 12.46, 95% CI: 7.40–21.0) were predictive of EC after adjustment for confounders. In-hospital diagnosis was predictive of LC, whereas being diagnosed more recently was protective against LC (HR: 0.96, 95% CI: 0.93–0.98).CONCLUSIONS:The cumulative incidence of colectomy in UC is lower than previously reported, and appears to be decreasing further among more recently diagnosed cohorts of patients. Male sex and hospitalization at the time of diagnosis are major risk factors for EC and LC.

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.

The Toronto Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy

BACKGROUND & AIMS The management of inflammatory bowel disease (IBD) poses a particular challenge during pregnancy because the health of both the mother and the fetus must be considered. METHODS A systematic literature search identified studies on the management of IBD during pregnancy. The quality of evidence and strength of recommendations were rated using the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. RESULTS Consensus was reached on 29 of the 30 recommendations considered. Preconception counseling and access to specialist care are paramount in optimizing disease management. In general, women on 5-ASA, thiopurine, or anti-tumor necrosis factor (TNF) monotherapy for maintenance should continue therapy throughout pregnancy. Discontinuation of anti-TNF therapy or switching from combination therapy to monotherapy may be considered in very select low-risk patients. Women who have a mild to moderate disease flare while on optimized 5-ASA or thiopurine therapy should be managed with systemic corticosteroid or anti-TNF therapy, and those with a corticosteroid-resistant flare should start anti-TNF therapy. Endoscopy or urgent surgery should not be delayed during pregnancy if indicated. Decisions regarding cesarean delivery should be based on obstetric considerations and not the diagnosis of IBD alone, with the exception of women with active perianal Crohns disease. With the exception of methotrexate, the use of medications for IBD should not influence the decision to breast-feed and vice versa. Live vaccinations are not recommended within the first 6 months of life in the offspring of women who were on anti-TNF therapy during pregnancy. CONCLUSIONS Optimal management of IBD before and during pregnancy is essential to achieving favorable maternal and neonatal outcomes.

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.

Proton pump inhibitors and the risk of hospitalisation for community-acquired pneumonia: replicated cohort studies with meta-analysis

Objective Previous observational studies suggest that the use of proton pump inhibitors (PPIs) may increase the risk of hospitalisation for community-acquired pneumonia (HCAP). However, the potential presence of confounding and protopathic biases limits the conclusions that can be drawn from these studies. Our objective was, therefore, to examine the risk of HCAP with PPIs prescribed prophylactically in new users of non-steroidal anti-inflammatory drugs (NSAIDs). Design We formed eight restricted cohorts of new users of NSAIDs, aged ≥40 years, using a common protocol in eight databases (Alberta, Saskatchewan, Manitoba, Ontario, Quebec, Nova Scotia, US MarketScan and the UKs General Practice Research Database (GPRD)). This specific patient population was studied to minimise bias due to unmeasured confounders. High-dimensional propensity scores were used to estimate site-specific adjusted ORs (aORs) for HCAP at 6 months in PPI patients compared with unexposed patients. Fixed-effects meta-analytic models were used to estimate overall effects across databases. Results Of the 4 238 504 new users of NSAIDs, 2.3% also started a PPI. The cumulative 6-month incidence of HCAP was 0.17% among patients prescribed PPIs and 0.12% in unexposed patients. After adjustment, PPIs were not associated with an increased risk of HCAP (aOR=1.05; 95% CI 0.89 to 1.25). Histamine-2 receptor antagonists yielded similar results (aOR=0.95, 95% CI  0.75 to 1.21). Conclusions Our study does not support the proposition of a pharmacological effect of gastric acid suppressors on the risk of HCAP.

The Relationship Between Proton Pump Inhibitor Use and Longitudinal Change in Bone Mineral Density: A Population-Based From the Canadian Multicentre Osteoporosis Study (CaMos)

OBJECTIVES:Proton pump inhibitor (PPI) use has been identified as a risk factor for hip and vertebral fractures. Evidence supporting a relationship between PPI use and osteoporosis remains scant. Demonstrating that PPIs are associated with accelerated bone mineral density (BMD) loss would provide supportive evidence for a mechanism through which PPIs could increase fracture risk.METHODS:We used the Canadian Multicentre Osteoporosis Study data set, which enrolled a population-based sample of Canadians who underwent BMD testing of the femoral neck, total hip, and lumbar spine (L1–L4) at baseline, and then again at 5 and 10 years. Participants also reported drug use and exposure to risk factors for osteoporosis and fracture. Multivariate linear regression was used to determine the independent association of PPI exposure and baseline BMD, and on change in BMD at 5 and 10 years.RESULTS:In all, 8,340 subjects were included in the baseline analysis, with 4,512 (55%) undergoing year 10 BMD testing. After adjusting for potential confounders, PPI use was associated with significantly lower baseline BMD at the femoral neck and total hip. PPI use was not associated with a significant acceleration in covariate-adjusted BMD loss at any measurement site after 5 and 10 years of follow-up.CONCLUSIONS:PPI users had lower BMD at baseline than PPI non-users, but PPI use over 10 years did not appear to be associated with accelerated BMD loss. The reasons for discordant findings between PPI use at baseline and during follow-up require further study.

Infectious and malignant complications of TNF inhibitor therapy in IBD.

Tumor necrosis factor (TNF) inhibitors are being increasingly utilized in the management of inflammatory bowel disease (IBD). Although the benefits associated with TNF inhibitor therapy are undeniable, concerns have been raised about the associated risk of infectious and malignant complications. In this narrative review, we will present the evidence from studies that have evaluated the association of TNF inhibitors and both overall and specific infections and malignancy. Overall, although TNF inhibitors may increase the risk of tuberculosis, varicella, and other opportunistic infections, there is little evidence suggesting that anti-TNF agents specifically raise the overall risk of serious infections. Similarly, there is little evidence that TNF antagonists raise the risk of developing malignancy over and above the risks from concomitant therapies and the underlying disease process. However, the risk of nonmelanoma skin cancers may be increased and that is further enhanced by use of combination TNF inhibitor and thiopurine therapy. The risk of non-Hodgkins lymphoma is statistically increased among combination therapy users. The absolute risk remains a very small but feared risk. It is difficult to fully quantify the risk of these cancers among users of TNF inhibitor therapy in the absence of concurrent thiopurine therapy. We recommend that clinicians remain mindful about the potential risks of infectious and malignant complications in their IBD patients who are using TNF inhibitors, but that further research is required to better study these risks over the long-term course of therapy.