title: Proton Pump Inhibitors, Histamine H2 Receptor Antagonists, and Other Antacid Medications and the Risk of Fracture Medication-Related Fall Incidents in an Older, Ambulant Population: The B-PROOF Study Risk Factors for Falls with Use of Acid-Suppressive Drugs Falls in the elderly: a prospective study of risk factors and risk profiles. The effect of proton pump inhibitors on fracture risk: report from the Canadian Multicenter Osteoporosis Study Magnitude and economic effect of overuse of antisecretory therapy in the ambulatory care setting. Long-term proton pump inhibitor therapy and falls and fractures in elderly women: a prospective cohort study.
abstract: We studied the effect of proton pump inhibitors , histamine H2 receptor antagonists , and other types of antacid drugs on  fracture risk . All cases were subjects with any fracture sustained during the year 2000 ( n = 124,655 ) . For each case , three controls ( n = 373,962 ) matched on age and gender were r and omly drawn from the background population . The primary exposure variables were use of proton pump inhibitors , histamine H2 antagonists , and other antacid drugs . Adjustments were made for several confounders , including diagnosis of an ulcer , nonsteroidal anti-inflammatory drug use , use of histamine H1 antagonists , stomach resection , previous fracture , and use of corticosteroids . The effect of dose was examined by stratifying for cumulated dose ( defined daily dose ) . Use of proton pump inhibitors was associated with an increase in fracture risk for use within the last year [ odds ratio ( OR ) = 1.18 , 95 % confidence interval ( CI ) 1.12–1.43 for overall fracture risk ; OR = 1.45 , 95 % CI 1.28–1.65 for hip fractures ; and OR = 1.60 , 95 % CI 1.25–2.04 for spine fractures ) . Histamine H2 antagonists were associated with a decreased fracture risk if they had been used within the last year ( OR = 0.88 , 95 % CI 0.82–0.95 for any fracture , OR = 0.69 , 95 % CI 0.57–0.84 for hip fractures ) . Other antacids were not associated with overall fracture risk but were associated with hip and spine fractures . Proton pump inhibitors appeared to be associated with a limited increase in fracture risk , in contrast to histamine H2 antagonists , which seemed to be associated with a small decrease in fracture risk . In all cases , the changes in risk estimates were small and the clinical significance was limited Background Medication use is a potentially modifiable risk factor for falling ;  psychotropic and cardiovascular drugs have been indicated as main drug groups that increase fall risk . However , evidence is mainly based on studies that recorded falls retrospectively and /or did not determine medication use at the time of the fall . Therefore , we investigated the associations indicated in the literature between medication use and falls , using prospect ively recorded falls and medication use determined at the time of the fall . Methods Data from the B-PROOF ( B-vitamins for the prevention of osteoporotic fractures ) study were used , concerning community-dwelling elderly aged ≥65 years . We included 2,407 participants with pharmacy dispensing records . During the 2- to 3-year follow-up , participants recorded falls using a fall calendar . Cox proportional hazard models were applied , adjusting for potential confounders including age , sex , health status variables and concomitant medication use . Results During follow-up , 1,147 participants experienced at least one fall . Users of anti-arrhythmic medication had an increased fall risk ( hazard ratio [ HR ] 1.61 ; 95 % confidence interval [ CI ] 1.12–2.32 ) compared with non-users . Similarly , non-selective beta-blocker use was associated with an increased fall risk ( HR 1.41 [ 95 % CI 1.12–1.78 ] ) , while statin use was associated with a lower risk ( HR 0.81 [ 95 % CI 0.71–0.94 ] ) . Benzodiazepine use ( HR 1.32 [ 95 % CI 1.02–1.71 ] ) , and antidepressant use ( HR 1.40 [ 95 % CI 1.07–1.82 ] ) were associated with an increased fall risk . Use of other cardiovascular and psychotropic medication was not associated with fall risk . Conclusion Our results strengthen the evidence for an increased fall risk in community-dwelling elderly during the use of anti-arrhythmics , non-selective beta-blockers , benzodiazepines , and antidepressant medication . Clinicians should prescribe these drugs cautiously and if possible choose safer alternatives for older patients 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 In this prospect i ve study , the authors determined intrinsic risk factors for falls and recurrent falls and constructed a risk profile that indicated the relative contribution of each risk factor and also estimated the probabilities of falls and recurrent falls . In 1992 , over a 28-week period , falls were recorded among 354 elderly subjects aged 70 years or over who were living in homes or apartments for the elderly in Amsterdam and the vicinity . During the study period , 251 falls were reported by 126 subjects ( 36 % ) , and recurrent falls ( > or = 2 falls ) were reported by 57 subjects ( 16 % ) . Associations of falls and recurrent falls with potential risk factors were identified in logistic regression models . Mobility impairment regarding one or more of the tested items ( i.e. , impairment of balance , leg-extension strength , and gait ) was associated with falls ( adjusted odds ratio ( OR ) = 2.6 ) and was strongly associated with recurrent falls ( OR = 5.0 ) . Dizziness upon st and ing was associated with falls ( OR = 2.1 ) and recurrent falls ( OR = 2.1 ) . However , several risk factors were associated with recurrent falls only : history of stroke ( OR = 3.4 ) , poor mental state ( OR = 2.4 ) , and postural hypotension ( OR = 2.0 ) . The authors constructed a risk profile for recurrent falls that included the five risk factors mentioned above . Inclusion of all risk factors in the profile implied an 84 % probability of recurrent falls over a period of 28 weeks , compared with 3 % when no risk factor was present . The probability of recurrent falls ranged only from 11 % to 29 % when predicted by number of falls occurring in the previous year . Physical activity , use of high-risk medication , and the use of vitamin D3 , which was r and omly allocated to the participants , were not strongly related to either falls or recurrent falls . In conclusion , a large range of probabilities of falls , especially of recurrent falls , was estimated by the risk profiles , in which mobility impairment was the major risk factor . Recurrent fallers may therefore be especially amenable to prevention based on mobility improvement 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 OBJECTIVES To determine the prevalence and economic effect of inappropriate proton pump inhibitor ( PPI ) use in an ambulatory care setting . STUDY DESIGN Retrospective medical record review of r and om sample with subgroup analysis . METHODS Patients were categorized according to appropriateness of pharmacotherapy  based on documented upper gastrointestinal tract diagnoses , gastrointestinal or extraesophageal symptoms , or gastroprotection . Adverse events potentially associated with PPI use were identified . RESULTS Of 946 patients in an ambulatory care setting , 35.4 % were given PPI therapy for an appropriately documented upper gastrointestinal tract diagnosis , 10.1 % received PPIs empirically for symptomatic treatment based on extraesophageal symptoms , 18.4 % received PPIs for gastroprotection , and 36.1 % had no documented appropriate indication for PPI therapy . In a subgroup analysis , 48.6 % of patients across all 4 categories received PPIs without documentation of reevaluation of upper gastrointestinal tract symptoms , accounting for 1034 patient-years of PPI use . The total cost of inappropriate PPI use was $ 233,994 based on over-the-counter PPI costs and $ 1,566,252 based on average wholesale price costs . Potentially related adverse events in this cohort included Clostridium difficile – associated diarrhea ( 6 cases ) and community-acquired pneumonia ( 1 case ) , but no cases of hip fracture or vitamin B12 deficiency were identified . CONCLUSIONS Proton pump inhibitors are often overused in the ambulatory care setting without documented valid indications . Inappropriate use of PPIs is associated with substantial cost expenditure and with the potential for adverse events 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
target: 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: 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 .