Long-term proton pump inhibitor therapy and falls and fractures in elderly women: a prospective cohort study. Appropriate proton pump inhibitor use among older adults: a retrospective chart review. Proton pump inhibitor-associated pneumonia: Not a breath of fresh air after all? Risk Factors for Falls with Use of Acid-Suppressive Drugs Proton-Pump Inhibitor Use and the Risk for Community-Acquired Pneumonia Angiotensin system-blocking medications are associated with fewer falls over 12 months in community-dwelling older people. Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study Proton pump inhibitors and vascular function: A prospective cross-over pilot study Proton Pump Inhibitors and the Risk of Adverse Cardiac Events Clinical trial: long‐term use of proton pump inhibitors in primary care patients – a cross sectional analysis of 901 patients Feasibility of a Patient-Centered Deprescribing Process to Reduce Inappropriate Use of Proton Pump Inhibitors The effect of proton pump inhibitors on fracture risk: report from the Canadian Multicenter Osteoporosis Study Effects of a multifactorial fall prevention program on fall incidence and physical function in community-dwelling older adults with risk of falls. Proton Pump Inhibitor Usage and the Risk of Myocardial Infarction in the General Population Hip fracture and proton pump inhibitor therapy: position statement. Inappropriate prescribing of proton pump inhibitors in primary care Impact of enhanced pharmacologic care on the prevention of falls: a randomized controlled trial.
Proton pump inhibitors ( PPIs ) are widely used in the elderly . Recent studies have suggested that long-term PPI therapy is associated with fractures in the elderly , however the mechanism remains unknown . We investigated the association between long-term PPI therapy ≥1 year and fracture risk factors including bone structure , falls , and balance-related function in a post hoc analysis of a longitudinal population -based prospect i ve cohort of elderly postmenopausal women and replicated the findings in a second prospect i ve study of falling in elderly postmenopausal women .  Long-term PPI therapy was associated with increased risk of falls and fracture-related hospitalizations ; adjusted odds ratio ( AOR ) 2.17 ; 95 % CI , 1.25 - 3.77 ; p = 0.006 and 1.95 ; 95 % CI , 1.20 - 3.16 ; p = 0.007 , respectively . In the replication study , long-term PPI use was associated with an increased risk of self-reported falling ; AOR , 1.51 ; 95 % CI , 1.00 - 2.27 ; p = 0.049 . No association of long-term PPI therapy with bone structure was observed ; however , question naire-assessed falls-associated metrics such as limiting outdoor activity ( p = 0.002 ) and indoor activity ( p = 0.001 ) due to fear of falling , dizziness ( p < 0.001 ) and numbness of feet ( p = 0.017 ) and objective clinical measurement such as Timed Up and Go ( p = 0.002 ) and Romberg eyes closed ( p = 0.025 ) tests were all significantly impaired in long-term PPI users . Long-term PPI users were also more likely to have low vitamin B12 levels than non-users ( 50 % versus 21 % , p = 0.003 ) . In conclusion , similar to previous studies , we identified an increased fracture risk in subjects on long-term PPI therapy . This increase in fracture risk in elderly women , already at high risk of fracture , appears to be mediated via increased falls risk and falling rather than impaired bone structure and should be carefully considered when prescribing long-term PPI therapy BACKGROUND Proton pump inhibitors ( PPIs ) are widely used , but not always with a clear indication . Nonindicated use is of particular concern among older adults , who may have multiple comorbidities and take more medications , increasing their risk for adverse drug reactions . OBJECTIVE This study examined the appropriateness of PPI use at an outpatient geriatric practice and the association between particular patient characteristics and appropriate use of these medications . METHODS This was a retrospective chart review of a group of r and omly identified community-dwelling adults aged > or=65 years with a current prescription for a PPI ( as of August 2006 ) from a geriatric ambulatory care practice within an urban academic medical center . The main outcome was appropriateness of PPI use , categorized as indicated , possibly indicated , or not indicated , based on US Food and Drug Administration-approved indications and national gastroenterology guidelines . RESULTS Out of approximately 2500 patients in the geriatric practice , 702 ( approximately 28 % ) were identified as having a current prescription for a PPI .  From these , 110 charts were r and omly selected for review , of which 10 were excluded based on predefined criteria . The sample was 79 % female and 46 % white , with a mean age of 82.8 years ( range , 66 - 99 years ) .  PPI use was indicated in 64 % of these patients , possibly indicated in 7 % , and not indicated in 29 % . Compared with indicated PPI use , nonindicated use was significantly associated with use for < 1 year ( relative risk = 2.20 ; 95 % CI , 1.00 - 4.86 ; P = 0.05 ) . Nonindicated PPI use was not significantly associated with age , female sex , nonwhite race , or PPI initiation in the inpatient setting . CONCLUSION Almost 30 % of patients receiving a PPI  in this academic geriatric practice had no documented indication for PPI use Over the past two decades , proton pump inhibitors ( PPIs ) have emerged as highly effective and relatively safe agents for the treatment of a variety of gastrointestinal disorders . Unfortunately , this desirable pharmacological profile has also contributed to superfluous and widespread use in both the inpatient and outpatient setting s. While generally well-tolerated , research published over the last decade has associated these agents with increased risks of Clostridium difficile disease , fractures likely due to calcium malabsorption and both community-acquired ( CAP ) and hospital-acquired pneumonias ( HAP ) . The mechanism behind PPI-associated pneumonia may be multifactorial , but is thought to stem from compromising the stomach 's " acid mantle " against gastric colonization of acid-labile pathogenic bacteria which then may be aspirated . A secondary postulate is that PPIs , through their inhibition of extra-gastric H(+)/K(+)-ATPase enzymes , may reduce the acidity of the upper aerodigestive tract , thus result ing in increased bacterial colonization of the larynx , esophagus and lungs . To date , several retrospective case control studies have been published looking at the association between PPI use and CAP . Some studies found a temporal relationship between PPI exposure and the incidence of pneumonia , but only two could define a dose-response relationship . Furthermore , other studies found an inverse correlation between duration of PPI use and risk of CAP . In terms of HAP , we review ed two retrospective cohort studies and one prospect i ve study . One retrospective study in a medical ICU found no increased association of HAP in PPI-exposed patients compared to no acid-lowering therapy , while the other in cardiothoracic surgery patients showed a markedly increased risk compared to those receiving H(2)RAs . The one prospect i ve study in ICU patients showed an increased risk of HAP with PPIs , but not with H(2)RAs . In conclusion , the current literature shows a slight trend toward an association between PPI use and pneumonia and an increased risk with PPIs over H(2)RAs , but the findings are not consistent across all studies . Larger controlled trials still need to be done to better identify the risk that PPIs impart towards patients contracting CAP or HAP . Until these are completed , we will have to continue to extrapolate across smaller controlled trials to predict the associated risks in our respective patient population s. In the interim , it appears prudent to limit the use of PPIs to situations where they are clinical ly indicated and , in such cases , use them at the lowest effective dose . In the case of prescribing for stress ulcer prophylaxis in ICU patients , perhaps H(2)RAs should be used as the preferred agents over PPIs Background : Some recent reports suggest an increased risk of fractures with use of proton pump inhibitors ( PPIs ) and histamine type 2 receptor antagonists ( H2RAs ) , although results are inconsistent and a causal relationship has yet to be proven . As these acid-suppressive drugs may have uncommon adverse effects on the central nervous system ( CNS ) , such as dizziness , we investigated whether their use is associated with falls as a possible mechanism for increasing fracture risk . Methods : A cohort study with nested case-control analysis and two validation strategies was performed using data from UK patients ( aged 40–89 years ) included in The Health Improvement Network data base ( 2000–2008 ) . Due to the large number of falls , a r and om sample of 20,000 cases was used for the analysis . Results : The overall incidence of falls per 1000 person-years was 13.0 ( 95 % confidence interval [ CI ] = 12.9–13.1 ) . After adjustment for potential confounders , there was no relationship between falls and current use of single PPIs ( odds ratio [ OR ] = 0.95 ; 95 % CI = 0.89–1.02 ) or H2RAs ( OR = 1.01 ; 95 % CI = 0.90–1.14 ) ; there was no relationship with dose or duration of treatment . Falls were associated with CNS disorders and treatment with various pharmacological agents including antiparkinson drugs ( OR = 2.7 ; 95 % CI = 2.2–3.3 ) and antiepileptics ( OR = 2.1 ; 95 % CI = 1.8–2.3 ) . Conclusions : There was no association between falls and use of PPIs or H2RAs . Any potential increase in the risk of fractures proposed to be associated with the use of acid-suppressive drugs is not via an increased risk of falls Context Some studies suggest that proton-pump inhibitors ( PPIs ) may increase risk for community-acquired pneumonia ( CAP ) .  Contribution This large , nested casecontrol study involving adults in general practice s in the United Kingdom found that current , long-term PPI use was not associated with increased risk for CAP . Recently started PPI therapy was associated with increased risk : Adjusted odds ratios for PPI use started within 2 , 7 , and 14 days of CAP diagnosis were 6.5 , 3.8 , and 3.2 , respectively . Implication Long-term PPI use is not associated with increased risk for CAP . The association between recently started PPIs and CAP risk is not clear but is not necessarily causal . The Editors Proton-pump inhibitors ( PPIs ) are potent gastric acid suppressants . With its excellent efficacy for acid-related diseases and increasing availability of both over-the-counter and generic formulations , PPI use continues to escalate ( 1 ) . Antiulcer drugs , primarily PPIs , ranked second in overall U.S. retail sales at $ 10.8 billion in 2001 ( 2 ) . Two studies recently suggested that PPI use may increase the risk for community-acquired pneumonia ( CAP ) ( 3 , 4 ) . A proposed mechanism is increased bacterial colonization in the upper gastrointestinal tract due to gastric acid suppression ( 3 , 4 ) . However , other noncausal mechanisms may also be responsible for the association between PPIs and CAP . Residual confounding may have contributed to the relatively modest increased risk seen in these studies . Furthermore , both studies found that the association was weakest among current recipients who had been taking PPIs for the longest duration , which is contrary to what one would expect if PPIs increase the risk for CAP . Community-acquired pneumonia leads to significant morbidity and mortality and dramatic costs to the health care system . In the United States , more than 1.1 million persons are hospitalized each year because of CAP ( 5 ) . In the Medicare program alone , more than $ 3.5 billion are spent on pneumonia-related admissions annually ( 5 ) . Given the widespread use of PPIs , clarifying the potential association between PPI therapy and risk for CAP is of great importance to public health . A recent systematic review on management strategies for gastroesophageal reflux disease , commissioned by the U.S. Agency for Healthcare Research and Quality , called for further studies to eluci date the role of acid suppression on the development of CAP ( 6 ) . Thus , we sought to more definitively examine the effect of current PPI exposure on CAP development in a large , population -based cohort . Methods Data Source We conducted a nested casecontrol study by using the General Practice Research Data base ( GPRD ) . The GPRD comprises prospect ively collected , computerized medical records from a sample of general practice s throughout the United Kingdom that represents the U.K. population in terms of age , sex , and geographic distribution ( 7 ) . Under the National Health Service , a general practitioner coordinates the health care of 98 % of U.K. residents . The GPRD differs fundamentally from cl aims data bases because it comprises the actual medical record , which contains complete and comprehensive clinical data . The information collected in the data base includes demographic characteristics , prescription use , clinical diagnoses , subspecialty consultation notes , and hospital discharge diagnoses . Prescriptions for most medications are written for 1 month in U.K. general practice s. Details of every prescription issued include date , dosage , quantity dispensed , duration of therapy , and indication . The Read clinical classification and the Oxford Medical Information System codes are used to classify medical diagnoses ( 8 , 9 ) . The Read clinical classification was adopted in the United Kingdom in 1990 as an electronic medical coding system . These codes incorporate information on medical history , physical examination , procedures , symptoms , medication use , and social history . These codes are cross-referenced with other major systems of medical coding , including but not limited to the International Classification of Diseases , Ninth and Tenth Revisions ( ICD-9 and ICD-10 ) , and Current Procedural Terminology-4 . The Oxford Medical Information System codes are related to the ICD-9 codes , with the first 3 numbers typically corresponding to the first 3 digits of the ICD-9 codes . The GPRD uses a practice -based quality marker known as up-to-st and ard to indicate when data recording by the practice adhered to specific quality measures according to GPRD Recording Guidelines , with respect to completeness , continuity , and plausibility ( 7 ) . We used only data that were collected after the up-to-st and ard date in each practice to maximize the validity of the study . Previous validation studies have shown that the GPRD captures 90 % to 95 % of the diagnoses from specialty referral visits and greater than 90 % of the principal hospital discharge diagnoses ( 1012 ) . The institutional review board at the University of Pennsylvania and the GPRD Independent Scientific Advisory Committee approved this study . The University of Pennsylvania 's institutional review board granted a waiver of informed consent because we used existing data that contained no patient identifiers . Study Cohort Study participants were drawn from a cohort of approximately 9 million patients who started follow-up in the GPRD from May 1987 to April 2002 . The Figure shows the cohort selection process and the exclusion criteria . A substantial proportion of patients met several exclusion criteria . We excluded patients who received a diagnosis of CAP within the initial 6 months of GPRD follow-up to avoid misclassification of prevalent CAP cases as incident cases ( 13 ) . We excluded patients receiving Helicobacter pylori eradication therapy  because their antibiotics concurrent with PPI therapy  could potentially mask the effect of PPI use on the risk for CAP . We excluded patients who received a diagnosis of aspiration pneumonia because it differs from CAP in terms of pathophysiology and risk factors . Only 1 % of case patients were excluded solely on the basis of this criterion . Figure . Study flow diagram . GPRD = General Practice Research Data base . * Some patients met multiple exclusion criteria . Case Patients Case patients consisted of all individuals in the eligible study cohort who received a diagnosis with their first episode of CAP within the GPRD follow-up period . The CAP diagnosis was determined on the basis of a list of relevant Read clinical classification or Oxford Medical Information System codes . The date of the first CAP diagnosis was design ated as the index date for each case . To improve the specificity of our CAP case patient definition , we did a secondary analysis in which we restricted our case-patient group to those who had a first episode of CAP in the GPRD that result ed in a hospital admission . A case of CAP was considered to have required hospitalization if the recorded diagnosis was linked with a hospitalization outcome code . Control Participants By using incidence density sampling , we r and omly selected up to 10 control participants for each case patient from the eligible study cohort . Incidence density sampling of control participants yields odds ratios ( ORs ) that are unbiased estimates of the incidence rate ratios ( 14 ) . Control participants were selected 1 case at a time with replacement ( that is , a patient can be a control participant for several cases ) . For each CAP case , we first identified all patients in the study cohort who remained at risk for CAP on the index date of the case . We then selected , among patients at risk , those who were followed at the same general practice site as the case . From those at-risk patients in the same practice site , we then selected patients who started GPRD follow-up on a date that is within 1 month before or after the GPRD start date of the case . Patients who fulfilled all criteria were eligible matched control participants and were assigned an index date that was the same as the case index date . By definition , all eligible control participants were matched to their respective case patients on index date , general practice site , and both calendar period and duration ( 1 month ) of follow-up before the index date . In the event that 10 or fewer eligible matched control participants were available for a particular case , all control participants were included . If more than 10 eligible matched control participants were available for a case , we r and omly selected 10 for our analysis . We then repeated the process for all case patients . We were able to identify 10 control participants for greater than 99 % of the cases and at least 1 eligible matched control participant for all cases . The reason for choosing 10 control participants was based on considerations for statistical power and efficiency of analysis . Generally , significant statistical power can be gained by going from a 1-to-1 to a 1-to-10 casecontrol ratio . There would be little further gain in statistical power , yet the computational time would increase significantly by increasing the controlcase ratio above 10 . Measure of Exposure The primary exposure of interest was current PPI therapy : use of any PPI ( esomeprazole , omeprazole , rabeprazole , pantoprazole , or lansoprazole ) within 30 days before the index date . Patients were considered to be exposed if they had a PPI prescription that would have lasted beyond 30 days before the index date . Among current PPI recipients , we examined the effect of daily dose ( 1.5 defined daily dose/d vs. > 1.5 defined daily dose/d ) ( 15 ) and duration of use before index date ( that is , < 30 days , 30 to 180 days , or > 180 days ) as a secondary analysis . We also did a sensitivity analysis by varying the current exposure window to 15 , 60 , 90 , and 120 days . Past recipients were those who were exposed to PPI therapy that ended more than 30 days before the index date in the primary analysis . Statistical Analysis We used conditional logistic OBJECTIVES To investigate relationships between the use of cardiovascular medications , including angiotensin system-blocking medications ( ASBMs ) , orthostatic hypotension ( OH ) , fall risk , and falls in community-dwelling older people . DESIGN Prospect i ve cohort study . SETTING Sydney , Australia . PARTICIPANTS Five hundred twenty community-dwelling older adults . MEASUREMENTS Medical , medication and falls history were obtained from a st and ardized question naire in all participants . Blood pressure was measured in supine , seated , and tilted positions . Fall risk was assessed using the Physiological Profile Assessment ( PPA ) . Falls data were collected prospect ively for 12 months using monthly fall calendars . Participants were defined as nonfallers ( no falls ) and fallers ( ≥ 1 falls ) at the end of the 12-month follow-up . RESULTS Participants taking medications affecting the angiotensin system had greater quadriceps strength , but after adjusting for sex , this difference became insignificant . People taking ASBMs were less likely to fall ( odds ratio = 0.68 , 95 % confidence interval = 0.48 - 0.97 ) , and the association between ASBMs and falls remained significant after adjusting for sex , body mass index , PPA score , and psychotropic medication and 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor ( statin ) use . OH was more frequently observed in participants taking alpha adrenergic receptor blockers ( α-blockers ) , but the presence of OH did not increase fall risk . CONCLUSION The use of cardiovascular medications in older people did not increase the risk of falls , and the use of ASBMs was associated with lower fall risk . The mechanisms for this apparent protective effect are unclear and appear not to be directly related to muscle strength . More research is required to eluci date the possible protective effects of certain cardiovascular medications in relation to falls in older people Objective To examine the association between chronic use of proton pump inhibitors ( PPIs ) and risk of hip fracture .  Design Prospect i ve cohort study . Setting Nurses ’ Health Study , which originally recruited from the 11 most populous states in the US . Participants 79 899 postmenopausal women enrolled in the Nurses ’ Health Study who provided data on the use of PPIs and other risk factors biennially since 2000 and were followed up to 1 June 2008 . Main outcome measure Incident hip fracture Results During 565 786 person years of follow-up , we documented 893 incident hip fractures . The absolute risk of hip fracture among regular users of PPIs was 2.02 events per 1000 person years , compared with 1.51 events per 1000 person years among non-users . Compared with non-users , the risk of hip fracture among women who regularly used PPIs for at least two years was 35 % higher ( age adjusted hazard ratio 1.35 ( 95 % confidence interval 1.13 to 1.62 ) ) , with longer use associated with increasing risk ( Ptrend<0.01 ) . Adjustment for risk factors , including body mass index , physical activity , and intake of calcium did not material ly alter this association ( hazard ratio 1.36 ( 1.13 to 1.63 ) ) . These associations were also not changed after accounting for reasons for PPI use . The relation between PPI use and fracture differed by smoking history ( Pinteraction=0.03 ) . Among current and former smokers , PPI use was associated with greater than 50 % increase in risk of fracture , with a multivariate hazard ratio for fracture of 1.51 ( 1.20 to 1.91 ) . In contrast , among women who never smoked there was no association ( multivariate hazard ratio 1.06 ( 0.77 to 1.46 ) ) . In a meta- analysis of these results with 10 prior studies , the pooled odds ratio of hip fracture associated with PPI use was 1.30 ( 1.25 to 1.36 ) . Conclusion Chronic use of PPIs is associated with increased risk of hip fracture  , particularly among women with a history of smoking Proton pump inhibitors ( PPIs ) are commonly used drugs for the treatment of gastric reflux . Recent retrospective cohorts and large data base studies have raised concern that the use of PPIs is associated with increased cardiovascular ( CV ) risk . However , there is no prospect i ve clinical study evaluating whether the use of PPIs directly causes CV harm . We conducted a controlled , open-label , cross-over pilot study among 21 adults aged 18 and older who are healthy ( n=11 ) or have established clinical cardiovascular disease ( n=10 ) . Study subjects were assigned to receive a PPI ( Prevacid ; 30 mg ) or a placebo pill once daily for 4 weeks . After a 2-week washout period , participants were crossed over to receive the alternate treatment for the ensuing 4 weeks . Subjects underwent evaluation of vascular function ( by the EndoPAT technique ) and had plasma levels of asymmetric dimethylarginine ( ADMA , an endogenous inhibitor of endothelial function previously implicated in PPI-mediated risk ) measured prior to and after each treatment interval . We observed a marginal inverse correlation between the EndoPAT score and plasma levels of ADMA ( r = −0.364 ) . Subjects experienced a greater worsening in plasma ADMA levels while on PPI than on placebo , and this trend was more pronounced amongst those subjects with a history of vascular disease . However , these trends did not reach statistical significance , and PPI use was also not associated with an impairment in flow-mediated vasodilation during the course of this study . In conclusion , in this open-label , cross-over pilot study conducted among healthy subjects and coronary disease patients , PPI use did not significantly influence vascular endothelial function . Larger , long-term and blinded trials are needed to mechanistically explain the correlation between PPI use and adverse clinical outcomes , which has recently been reported in retrospective cohort studies Background Recent evidence suggests that proton pump inhibitors ( PPIs ) might be linked with adverse cardiac events , but a causal relationship is unproven . Methods We applied the self-matched case series method to two studies using population -based health care data from Ontario , Canada between 1996 and 2008 . The first included subjects aged 66 years or older hospitalized for acute myocardial infa rct ion within 12 weeks following initiation of PPI , while the second included subjects hospitalized for heart failure . In both studies we design ated the primary risk interval as the initial 4 weeks of therapy and the control interval as the final 4 weeks . To test the specificity of our findings we examined use of histamine H2 receptor antagonists and benzodiazepines , drugs with no plausible causal link to adverse cardiac events . Results During the 13-year study period , we identified 5550 hospital admissions for acute myocardial infa rct ion and 6003 admissions for heart failure within 12 weeks of commencing PPI therapy . In the main analyses , we found that initiation of a PPI was associated with a higher risk of acute myocardial infa rct ion ( odds ratio 1.8 ; 95 % confidence interval 1.7 to 1.9 ) and heart failure ( odds ratio 1.8 ; 95 % confidence interval 1.7 to 1.9 ) . However , secondary analyses revealed similar risk estimates histamine H2 receptor antagonists and benzodiazepines , drugs with no known or suspected association with adverse cardiac events . Conclusion PPIs are associated with a short-term risk of adverse cardiac events , but similar associations are seen with other drugs exhibiting no known cardiac toxicity . Collectively these observations suggest that the association between PPIs and adverse cardiac events does not represent reflect cause- and -effect Background The use of proton pump inhibitors ( PPIs ) is extensive . While the incidence of new treatments remains stable , the prevalence of long‐term treatment is rising . Studies have shown that up to 70 % of patients on chronic acid suppression lack a verified indication for treatment Background : Proton pump inhibitors ( PPIs ) are inappropriately prescribed in up to 50 % of users . Systematic medication review and cessation of inappropriate medications or deprescribing may improve patient outcomes and reduce costs . Objective : The aim of this study was to assess the feasibility of a patient-centered deprescribing process in a population of adults with complex polypharmacy . Methods : This was a prospect i ve feasibility study . Participants were recruited from hospital outpatient clinics . The patient-centered deprescribing process consisted of 5 steps : comprehensive medication history , identification of potentially inappropriate medications , determining if the medication can be ceased , planning the withdrawal regimen ( eg , tapering where necessary ) , and provision of monitoring , support , and documentation . Feasibility was determined by assessing time taken to complete the different steps of the deprescribing process and participant feedback . Results : In all , 57 PPI users were recruited ; participants were 70 ± 14 years old and took 14 ± 6 medications . The indication for PPI use was verified in 43 participants and judged as potentially inappropriate in 19 ( 44 % ) ; 8 were suitable for trial withdrawal , and 6 consented . All 6 successfully ceased ( n = 3 ) or reduced ( n = 3 ) their PPI use , and this was sustained at 6 months postintervention in 4 participants . Conclusions : The patient-centered deprescribing process can safely reduce inappropriate PPI prescribing in a small proportion of people . Although the process was acceptable to participants , difficulties in accessing complete medical histories , time limitations , and minimal evidence to support effectiveness in certain indications were barriers to implementation of the process in clinical practice Summary A large Canadian cohort was studied over 10 years to see if proton pump inhibitor ( PPI ) use increased the risk of sustaining a fragility fracture . We found an increased risk of fracture in individuals who used PPIs .  The risk remained after controlling for other known fracture risk factors . Introduction Multiple retrospective studies have linked proton pump inhibitor use with increased risk of fragility fracture . We prospect ively studied the association between PPI use and fracture in a large cohort over a 10-year period while controlling for known fracture risk factors . Methods We studied 9,423 participants in the Canadian Multicenter Osteoporosis Study . The cohort was formed in 1995–1997 and followed for 10 years with monitoring for incident nontraumatic fracture and PPI use . Cox regression analyses were used to assess the association between  PPI  use and incident fracture risk . Results PPI use , coded as a time-dependent variable , was associated with a shorter time to first nontraumatic fracture , hazard ratio ( HR ) = 1.75 ( 95 % confidence interval ( CI ) 1.41–2.17 , p < 0.001 ) . After controlling for multiple risk factors , including femoral neck bone density , the association remained significant , HR = 1.40 ( 95 % CI 1.11–1.77 , p = 0.004 ) . Similar results were obtained after controlling for bisphosphonate use , using PPI “ ever ” use , or when the outcome was restricted to hip fracture . Conclusions In this large prospect i ve population -based cohort study , we found an association between PPI use and increased risk of fragility fracture . Although the increased risk found was modest , this finding is important , given the high prevalence of PPI use and the excess morbidity and mortality associated with osteoporosis-related fractures OBJECTIVE To evaluate effects of a multifactorial fall prevention program on fall incidence and physical function in community-dwelling older adults . DESIGN Multicenter r and omized controlled trial . SETTING Three medical centers and adjacent community health centers . PARTICIPANTS Community-dwelling older adults ( N=616 ) who have fallen in the previous year or are at risk of falling . INTERVENTIONS After baseline assessment , eligible subjects were r and omly allocated into the intervention group ( IG ) or the control group ( CG ) , stratified by the Physiological Profile Assessment ( PPA ) fall risk level . The IG received a 3-month multifactorial intervention program including 8 weeks of exercise training , health education , home hazards evaluation/modification , along with medication review and ophthalmology/other specialty consults . The CG received health education brochures , referrals , and recommendations without direct exercise intervention . MAIN OUTCOME MEASURES Primary outcome was fall incidence within 1 year . Secondary outcomes were PPA battery ( overall fall risk index , vision , muscular strength , reaction time , balance , and proprioception ) , Timed Up & Go ( TUG ) test , Taiwan version of the International Physical Activity Question naire , EuroQol-5D , Geriatric Depression Scale ( GDS ) , and the Falls Efficacy Scale-International at 3 months after r and omization . RESULTS Participants were 76±7 years old and included low risk 25.6 % , moderate risk 25.6 % , and marked risk 48.7 % .  The cumulative 1-year fall incidence was 25.2 % in the IG and 27.6 % in the CG ( hazard ratio=.90 ; 95 % confidence interval , .66 - 1.23 ) . The IG improved more favorably than the CG on overall PPA fall risk index , reaction time , postural sway with eyes open , TUG test , and GDS , especially for those with marked fall risk . CONCLUSIONS The multifactorial fall prevention program with exercise intervention improved functional performance at 3 months for community-dwelling older adults with risk of falls , but did not reduce falls at 1-year follow-up . Fall incidence might have been decreased simultaneously in both groups by heightened awareness engendered during assessment s , education , referrals , and recommendations Background and Aims Proton pump inhibitors ( PPIs ) have been associated with adverse clinical outcomes amongst  clopidogrel users after an acute coronary syndrome . Recent pre- clinical results suggest that this risk might extend to subjects without any prior history of cardiovascular disease . We explore this potential risk in the general population via data -mining approaches . Methods Using a novel approach for mining clinical data for pharmacovigilance , we queried over 16 million clinical documents on 2.9 million individuals to examine whether  PPI  usage was associated with  cardiovascular risk in the general population . Results In multiple data sources , we found gastroesophageal reflux disease ( GERD ) patients exposed to PPIs to have a 1.16 fold increased association ( 95 % CI 1.09–1.24 ) with myocardial infa rct ion ( MI ) . Survival analysis in a prospect i ve cohort found a two-fold ( HR = 2.00 ; 95 % CI 1.07–3.78 ; P = 0.031 ) increase in association with cardiovascular mortality . We found that this association exists regardless of clopidogrel use . We also found that H2 blockers , an alternate treatment for GERD , were not associated with increased cardiovascular risk ; had they been in place , such pharmacovigilance algorithms could have flagged this risk as early as the year 2000 . Conclusions Consistent with our pre- clinical findings that PPIs may adversely impact vascular function , our data -mining study supports the association of PPI exposure with risk for MI in the general population . These data provide an example of how a combination of experimental studies and data -mining approaches can be applied to prioritize drug safety signals for further investigation There has been recent media attention to the possibility that long-term proton pump inhibitor ( PPI ) prescribing may be linked to an increased risk of hip fracture  according to data from the United Kingdom ( UK ) ( 1 ) and Canada ( 2 ) . The Canadian Association of Gastroenterology has prepared the following position statement on the association between PPI therapy and hip fracture in light of this evidence . The present position statement is outlined in greater detail elsewhere ( 3 ) . Yang et al ( 1 ) reported a nested case-control study using the UK General Practice Research Data base that selected patients older than 50 years of age with an incident hip fracture , and age and sex-matched controls . There were 13,556 hip fracture cases and 135,386 controls ;  PPI therapy for more than one year was associated with an increased risk of hip fracture ( adjusted OR 1.44 ; 95 % CI 1.30 to 1.59 ) . Targownik et al ( 2 ) reported a further nested case-control study using the Manitoba Population Health Research Data Repository , in which 15,792 patients with osteoporosis-related fractures were compared with 47,289 controls . There was no overall association between  PPI use and fracture until after five or more years of exposure , when the risk of osteoporotic fracture became significant ( adjusted OR 1.62 ; 95 % CI 1.02 to 2.58 ) . Similarly , the risk of hip fracture became significant after seven years of PPI exposure ( adjusted OR 4.55 ; 95 % CI 1.68 to 12.29 ) . The clinical significance of this is uncertain because extrapolation of these figures ( assuming 1.8 per 1000 patients develop a hip fracture [ 1 ] ) suggests that 1263 patients need to be treated with a PPI for more than one year to develop one excess hip fracture , although the number needed to harm may be much lower after seven years according to the Canadian study . These studies use reputable data bases and are rigorously conducted and analyzed appropriately . The discussion s in both of these articles suggest quite strongly that the association they have found is likely to be causal . Large data bases provide a wonderful opportunity to evaluate benefits and harms of medical interventions , but caution must be exercised before assuming the latest finding represents a risk to patients . The ready availability of data bases means that literally millions of associations can be tested ; even within a particular hypothesis there are a variety of approaches to splitting the data ( eg , duration of therapy , therapy dose , length of follow-up , patient age , male versus female ) . Research ers and journals are prone to emphasize positive findings and tend to underplay the role of chance or confounding factors . These issues are less likely to be important if a consistent association is found . An accompanying editorial ( 4 ) to the Canadian study also cites a third Danish data base study ( 5 ) that supports an association between PPI therapy and fracture . It is interesting to note that the Danish study had a much greater number of cases ( 124,655 ) than the other two studies , and yet had much more muted conclusions and was published in a lower impact factor journal . The Danish study was circumspect in their conclusions because there were inconsistencies in the data and there was no dose response information . For example , there seemed to be an increased risk with taking less than 25 doses of a PPI in one year with a lower ( but still statistically significant ) risk in those taking one dose per day for a year . There seemed to be no biologically plausible hypothesis why such infrequent use of PPI therapy would be associated with an increased risk of fracture . There were also inconsistencies with the UK and Canadian studies . The UK study reported an increased risk of hip fracture after one year of PPI therapy ; there seemed to be little increase in risk over the next four years , whereas the Canadian study only found a significant association after seven years . Targownik et al ( 2 ) suggest that perhaps the UK data base included patients that had in fact been taking PPIs for much longer ; however , this is speculation . Furthermore , a Canadian cohort study ( 6 ) followed-up on elderly patients in Ontario on  warfarin ( n=52,701 ) , thyroid replacement  ( n=40,555 ) , oral corticosteroid ( n=43,915 ) and PPI therapy  ( n=60,383 ) for five years . There was no increased risk of hip fracture in those taking warfarin compared with those on PPI therapy ( adjusted OR 0.94 ; 95 % CI 0.81 to 1.09 ) , but there was an increased risk with  corticosteroid therapy compared with PPI therapy ( adjusted OR 1.44 ; 95 % CI 1.21 to 1.70 ) . It could be that warfarin is also associated with an increased risk of hip fracture ; however , it is interesting that Targownik et al ( 2 ) found little increase in fracture risk in those taking anticoagulants ( 14.5 % of fracture cases taking anticoagulants compared with 13.4 % of controls ) . The CAG is proud to acknowledge its Benefactor Corporate Sponsors : Abbott Canada AstraZeneca Canada Inc Axcan Pharma Inc Olympus Canada Inc Pentax Canada Inc. Procter & Gamble Pharmaceuticals Schering-Plough Canada Inc. UCB Pharma Inc. Finally , there is the issue of biological plausibility . It has been proposed that acid suppression may reduce calcium absorption and increase the risk of fracture ( 1 ) . The role of pH in calcium absorption is , however , controversial . The dissolution of calcium carbonate is pH-dependent in vitro , although the clinical significance of this is uncertain given that calcium is absorbed in the small intestine where the pH is nonacidic regardless of stomach pH. A review of the literature ( 7 ) identified seven r and omized trials that evaluated calcium absorption with acid suppression in healthy subjects or those with ulcer disease . There were major method ological issues with many of the studies and they were all small . Four studies found no impact on calcium absorption while three reported decreased absorption . Further work is needed in this area , but there are no conclusive data that would make the association between fracture and PPI biologically plausible . Furthermore , some research suggests that PPI therapy may inhibit bone resorption ( 8) , which may protect against fracture risk . PPIs are one of the most well-tolerated classes of drugs on the market . They have also improved the quality of life of countless patients with acid-related disease . There are risks in prescribing any drug and this should be borne in mind by all prescribing clinicians . PPI therapy should only be prescribed for indications where there is a proven or likely benefit and the need for these drugs should be review ed on a regular basis . This applies particularly to frail and elderly patients with multiple comorbidities and those taking a number of different medications where the possibility for drug interactions increases . This message applies to all the drugs clinicians prescribe including PPI therapy . Current data would not support particular care in prescribing PPI therapy due to concerns about the risk of hip fracture . There is no persuasive evidence that the association is causal , although this can never be excluded as a possibility . The Canadian Association of Gastroenterology encourages health professionals to keep continually up date d on the medical literature and will endeavour to disseminate further guidance if more information on the possible harms of PPI therapy becomes available Objectives : To determine if an educational intervention initiated in secondary care can influence prescribing of proton pump inhibitors  ( PPIs ) in the community . Methods : A prospect i ve study of  PPI use in patients admitted to medical wards in a university hospital . A simple educational intervention was employed to reduce inappropriate prescribing of PPIs in the community . Results : In the pre-intervention analysis 66/271 ( 24 % ) patients were receiving treatment with a PPI prescribed in the community . In 36/66 ( 54 % ) patients the PPI had been prescribed inappropriately . Six months after the intervention 91/344 ( 26 % ) patients were prescribed a PPI in the community . In only 45 of these 91 ( 49 % ) patients was there a recommended indication . Conclusion : The intervention used in this study had no effect on the proportion of patients taking a PPI  at the time of hospital admission or on the appropriateness of prescribing in the community BACKGROUND Falls are the leading cause of both fatal and nonfatal injuries among older adults in the United States . Medications that affect the central nervous system are known to increase the risk of falling . OBJECTIVE The purpose of this study was to assess the effects of a community pharmacy-based falls-prevention program targeting high-risk older adults on the rates of recurrent falls , injurious falls , and filling prescriptions for medications that have been associated with an increased risk of falling . METHODS This was a r and omized controlled trial of participants recruited through a community pharmacy chain in North Carolina . The 2-year study consisted of a 1-year " look-back " period before r and omization and a 1-year follow-up period after r and omization . Patients were eligible to participate if they were ≥65 years of age , had fallen at least once during the 1-year period preceding enrollment , and were taking medications associated with an increased risk of falling . Medications classified as high risk included benzodiazepines , antidepressants , anticonvulsants , sedative hypnotics , opioid analgesics , antipsychotics , and skeletal muscle relaxants . Participants were assigned to either the intervention arm or the control arm ; participants in the intervention arm were invited to attend a face-to-face medication consultation conducted by a community pharmacy resident , whereas those in the control arm received no medication consultation . The primary end point was the rate of recurrent falls during the 1-year followup period . Secondary end points were the total number of prescriptions for high-risk medications filled during the follow-up period and either discontinued use or a reduction in the dosage of a high-risk medication during the follow-up period . RESULTS One hundred eighty-six patients ( 132 women , 54 men ; 88.7 % white ) were enrolled . Intention-to-treat ( ITT ) analyses revealed no significant differences in the rates of recurrent falls , injurious falls , or filling prescriptions for high-risk medications . However , 13 patients in the intervention group either discontinued use of a high-risk medication or had the dosage reduced during the follow-up period , compared with 5 patients in the control group ( χ(2 ) = 3.94 ; P < 0.05 ) . As-treated analyses revealed numeric reductions in the rates of falls ( rate ratio [ RR ] = 0.76 ; 95 % CI , 0.53 - 1.09 ) , injurious falls ( RR= 0.67 ; 95 % CI , 0.43 - 1.05 ) , and filling prescriptions for high-risk medications ( RR= 0.85 ; 95 % CI , 0.72 - 1.03 ) after receipt of the intervention , but the differences were not statistically significant . CONCLUSIONS Results of this study support the feasibility of using community pharmacies to deliver a falls-prevention program targeting high-risk older adults . Although the ITT analyses revealed no significant reduction in the rate of recurrent falls , injurious falls , or overall use of high-risk medications , individuals in the intervention group were more likely than those in the control group to discontinue use of a high-risk medication or have the dosage reduced during the 1-year follow-up period . More work is needed to evaluate the intervention using a larger sample size that provides greater power to detect clinical ly meaningful effects of reduction in the use of high-risk medications on preventing or reducing falls in the high-risk population
Conclusions We demonstrate a significant association between the use of PPIs and increased risk of fall .
In addition , there is potentially higher risk of fall among PPIs users over time
Background Fall prevention among older adults is a worldwide public health advocacy because of negative consequences of fall .
Recent studies have shown that proton pump inhibitors ( PPIs ) increase the risk of fall .
PPIs are among the widely prescribed medications oftentimes without clear indications .
Concerns for safety of long-term use of PPIs have been raised by numerous studies .