title: Do Proton Pump Inhibitors Decrease Calcium Absorption? The effects of risedronate administered in combination with a proton pump inhibitor for the treatment of osteoporosis Proton Pump Inhibitors, Histamine H2 Receptor Antagonists, and Other Antacid Medications and the Risk of Fracture Hip fracture and proton pump inhibitor therapy: position statement. Bone density in proton pump inhibitors users: a prospective study Increase in Vertebral Fracture Risk in Postmenopausal Women Using Omeprazole Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study 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. Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women: results from the Women's Health Initiative. Does frailty predict increased risk of falls and fractures? A prospective population-based study A comparison of frailty indexes for the prediction of falls, disability, fractures, and mortality in older men. Long-term proton pump inhibitor therapy and falls and fractures in elderly women: a prospective cohort study.
abstract: Proton pump inhibitors ( PPIs ) increase  osteoporotic fracture  risk presumably via hypochlorhydria and consequent reduced fractional calcium absorption ( FCA ) . Existing studies provide conflicting information regarding the direct effects of PPIs on FCA . We evaluated the effect of PPI therapy on FCA . We recruited women at least 5 years past menopause who were not taking acid suppressants . Participants underwent three 24-hour inpatient FCA studies using the dual stable isotope method . Two FCA studies were performed 1 month apart to establish baseline calcium absorption . The third study occurred after taking omeprazole ( 40 mg/day ) for 30 days . Each participant consumed the same foods during all FCA studies ; study meals replicated subjects ' dietary habits based on 7-day diet diaries . Twenty-one postmenopausal women ages 58 ± 7 years ( mean ± SD ) completed all study visits . Seventeen women were white , and 2 each were black and Hispanic . FCA ( mean ± SD ) was 20 % ± 10 % at visit 1 , 18 % ± 10 % at visit 2 , and 23 % ± 10 % following 30 ± 3 days of daily omeprazole ( p = .07 , ANOVA ) . Multiple linear regression revealed that age , gastric pH , serum omeprazole levels , adherence to omeprazole , and 25-hydroxyvitamin D levels were unrelated to changes in FCA between study visits 2 and 3 . The 1,25-dihydroxyvitamin D3 level at visit 2 was the only variable ( p = .049 ) associated with the change in FCA between visits 2 and 3 . PPI-associated hypochlorhydria does not decrease FCA following 30 days of continuous use . Future studies should focus on identifying mechanisms by which PPIs increase the risk of osteoporotic fracture . © 2010 American Society for Bone and Mineral Research This study was performed to investigate the effects of the co-administration of proton pump inhibitor ( PPI ) on the efficacy of bisphosphonate ( BP ) treatment for osteoporosis . A total of 180 women with low bone mineral density were r and omly divided into four groups , one in which sodium risedronate was administered with sodium rabeprazole and one in which only risedronate was administered ( BP + PPI and BP groups , respectively ) . The biomarkers were measured at the baseline and every 3 months , inlcuding : N-terminal telopeptide of type I collagen corrected for creatinine , bone-specific alkaline phosphatase ( BAP ) , parathyroid hormone , bone mineral density ( BMD ) of the lumbar spine and physical parameters evaluated according to the SF-36v2 ™ Health Survey . Statistical comparisons of these parameters were performed after 9 months . Data were available for a total of 137 patients ( 62 in the BP group and 75 in the BP + PPI group ) . The Δ % value of increase in BMD and improvement of physical functioning in the BP + PPI group were significantly larger , and its decrease in BAP in the BP + PPI group was significantly smaller than that in the BP group . It is expected that risedronate administration in combination with a PPI may be more effective not only for treating osteoporosis but also improving physical fitness than treatment with risedronate alone 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 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 Patients with gastroesophageal reflux disease ( GERD ) receive long-term therapy with proton pump inhibitor ( PPI ) agents . Several studies have recently been published suggesting that treatment with PPI may cause bone fractures , although the number of prospect i ve studies in this regard is limited . The aim of this study is to prospect ively investigate the effect of PPIs on bone density . Between March 2009 and January 2011 , 114 GERD patients ( 18–56 years ) and 110 healthy controls were included in the present study .  Bone mineral densitometry ( BMD ) by using dual-energy X-ray absorptiometry was assessed at lumbar spine and femur neck . BMD measurements were performed on all subjects at the beginning of the study . The patients were divided according to three drugs by their treatment with esomeprazole , lansoprazole , or pantoprazole . The study group was followed for at least 6 months on PPI therapy , and then BMD measurements were repeated . The mean duration of treatment with PPIs was 8.5 ± 2.3 months . In patients receiving PPIs , the mean reduction in total vertebra T score following treatment compared to pre-treatment values was 00.23 ± 0.42 units ( 95 % CI 0.15–0.30 ) ( p < 0.01 ) , while the mean reduction in the femur T score was 0.10 ± 0.40 units ( 95 % CI 0.03–0.18 ) ( p = 0.03 ) . Reduction following treatment in L4 and total vertebra T scores of lansoprazole group was significantly higher than of pantoprazole group ( p = 0.04 ) . Reduction in femur T score of esomeprazole group was higher than of lansoprazole group and pantroprazole group , but it is not statistically significant . Treatment with a PPI results in a significant reduction in bone density . Close monitoring is beneficial for patients who are to receive long-term treatment with PPI Proton pump inhibitors are taken by millions of patients for prevention and treatment of gastroesophageal diseases . Case-control studies have suggested that use of omeprazole is associated with an increased risk of hip fractures . The aim of this prospect i ve study was to assess the risk of vertebral fractures in postmenopausal women using omeprazole .  We studied 1,211 postmenopausal women enrolled in the Osteoporosis and Ultrasound Study from the general population . Information on omeprazole and other risk factors for fractures including prevalent fractures and bone mineral density was obtained at baseline . Vertebral fractures were assessed on X-rays obtained at baseline and at the end of the 6-year follow-up and analyzed central ly . At baseline , 5 % of this population was using omeprazole .  Age-adjusted rates for vertebral fractures were 1.89 and 0.60 for 100 person-years for omeprazole users and nonusers , respectively ( P = 0.009 ) . In the multivariate analysis , omeprazole use was a significant and independent predictor of vertebral fractures ( RR = 3.50 , 95 % CI 1.14–8.44 ) . The other predictors were age higher than 65 years ( RR = 2.34 , 95 % CI 1.02–5.34 ) , prevalent vertebral fractures ( RR = 3.62 , 95 % CI 1.63–8.08 ) , and lumbar spine T score ≤ −2.5 ( RR = 2.38 , 95 % CI 1.03–5.49 ) . Omeprazole use is associated with an increased risk of vertebral fractures in postmenopausal women . Further studies are required to determine the mechanism of the association between the underlying gastric disease , omeprazole  use , and  risk of osteoporotic fractures 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 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 BACKGROUND Proton pump inhibitor ( PPI ) medications have been inconsistently shown to be associated with  osteoporotic fractures .  We examined the association of PPI use with bone outcomes ( fracture , bone mineral density [ BMD ] ) . METHODS This prospect i ve analysis included 161 806 postmenopausal women 50 to 79 years old , without history of hip fracture , enrolled in the Women 's Health Initiative ( WHI ) Observational Study and Clinical Trials with a mean ( SD ) follow-up of 7.8 ( 1.6 ) years . Analyses were conducted for 130 487 women with complete information .  Medication information was taken directly from drug containers during in-person interviews ( baseline , year 3 ) . The main outcome measures were self-reported fractures ( hip [ adjudicated ] , clinical spine , forearm or wrist , and total fractures ) and for a sub sample ( 3 densitometry sites ) , 3-year change in BMD . RESULTS During 1 005 126 person-years of follow-up , 1500 hip fractures , 4881 forearm or wrist fractures , 2315 clinical spine fractures , and 21 247 total fractures occurred . The multivariate-adjusted hazard ratios for current PPI use were 1.00 ( 95 % confidence interval [ CI ] , 0.71 - 1.40 ) for hip fracture , 1.47 ( 95 % CI , 1.18 - 1.82 ) for clinical spine fracture , 1.26 ( 95 % CI , 1.05 - 1.51 ) for forearm or wrist fracture , and 1.25 ( 95 % CI , 1.15 - 1.36 ) for total fractures . The BMD measurements did not vary between PPI users and nonusers at baseline . Use of PPIs was associated with only a marginal effect on 3-year BMD change at the hip ( P = .05 ) but not at other sites . CONCLUSION Use of PPIs was not associated with hip fractures but was modestly associated with clinical spine , forearm or wrist , and total fractures Summary A frailty concept that includes psychological and cognitive markers was prospect ively shown to be associated with increased risk of multiple falls and fractures among 1,509 community dwelling older adults , especially in those aged 75 and over . The predictive ability of frailty is not superior to falls history . Introduction The concept of frailty has been defined with or without psychological and cognitive markers . Falls are associated with multiple risk factors , including cognitive and mood disorders . The purpose of this study was to investigate the association of a comprehensive concept of frailty and its components with falls and fractures in community-dwelling older adults and to compare its predictive ability with having a history of falls . Methods One thous and five hundred nine participants in the Longitudinal Aging Study Amsterdam aged ≥65 were assessed to determine fall history and the prevalence of nine frailty markers , including cognitive and psychological factors . The number of falls and time to second fall were prospect ively registered for 1 year . Fractures were registered for 6 years . Results Frailty was significantly associated with time to second fall : hazard ratio of 1.53 [ 95 % confidence interval ( CI ) , 1.07–2.18 ] and area under the receiver operating characteristic curve ( AUC ) of 0.58 ( CI , 0.53–0.62 ) . In participants aged ≥75 , frailty was associated with ≥2 falls : odds ratio ( OR ) of 1.74 ( CI , 1.19–2.55 ) and AUC of 0.62 ( CI , 0.55–0.68 ) . Frailty , adjusted for age and sex , was significantly associated with ≥2 fractures : OR of 3.67 ( CI , 1.47–9.15 ) . The AUCs for falls history ( aged ≥75 ) ranged from 0.62 ( CI , 0.58–0.67 ) for ≥1 falls to 0.67 ( CI , 0.59–0.74 ) for ≥3 falls . Conclusions A concept of frailty including psychological and cognitive markers is associated with both multiple falls and fractures . However , frailty is not superior to falls history for the selection of old persons at increased risk of recurrent falls OBJECTIVES To compare the validity of a parsimonious frailty index ( components : weight loss , inability to rise from a chair , and poor energy ( Study of Osteoporotic Fractures ( SOF ) index ) ) with that of the more complex Cardiovascular Health Study ( CHS ) index ( components : unintentional weight loss , low grip strength , poor energy , slowness , and low physical activity ) for prediction of adverse outcomes in older men . DESIGN Prospect i ve cohort study . SETTING Six U.S. centers . PARTICIPANTS Three thous and one hundred thirty-two men aged 67 and older . MEASUREMENTS Frailty status categorized as robust , intermediate stage , or frail using the SOF index and criteria similar to those used in CHS index . Falls were reported three times for 1 year . Disability ( > or=1 new impairments in performing instrumental activities of daily living ) ascertained at 1 year . Fractures and deaths ascertained during 3 years of follow-up . Analysis of area under the receiver operating characteristic curve ( AUC ) statistics compared for models containing the SOF index versus those containing the CHS index . RESULTS Greater evidence of frailty as defined by either index was associated with greater risk of adverse outcomes .  Frail men had a higher age-adjusted risk of recurrent falls ( odds ratio (OR)=3.0 - 3.6 ) , disability ( OR=5.3 - 7.5 ) , nonspine fracture ( hazard ratio (HR)=2.2 - 2.3 ) , and death ( HR=2.5 - 3.5 ) ( P<.001 for all models ) . AUC comparisons revealed no differences between models with the SOF index and models with the CHS index in discriminating falls ( AUC=0.63 , P=.97 ) , disability ( AUC=0.68 , P=.86 ) , nonspine fracture ( AUC=0.63 , P=.90 ) , or death ( AUC=0.71 for model with SOF index and 0.72 for model with CHS index , P=.19 ) . CONCLUSION The simple SOF index predicts risk of falls , disability , fracture , and mortality in men as well as the more-complex CHS index 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: The magnitude of the association is modest and is most likely due to confounding factors as patients prescribed PPI therapy  tend to be more frail with more risk factors for fractures than those not given these drugs .
  There is no clear dose – response relationship and there is no association between PPI therapy and risk of fracture in those at highest risk .
  Finally , there is no clear mechanism through which PPI therapy increases the risk of fracture , as recent r and omized trials show no impact of PPI therapy on calcium absorption and there is no association between PPI therapy and risk of osteoporosis .
  We therefore feel there is insufficient evidence to change PPI prescribing habits based on risk of fracture .
  There is no evidence to support prescription of calcium and /or vitamin D in patients simply because they are taking PPI therapy .
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