2Literature Review Title: PPIs and Risk for Bone Fractures Peter R. McNally, DO, FACP, FACGUniversity Colorado DenverSchool of MedicineCenter for Human SimulationAurora, Colorado 80045
3Proton Pump Inhibitor Use, Hip Fracture, Shelly L. Gray, PharmD, MS; Andrea Z. LaCroix, PhD; Joseph Larson, MS; John Robbins, MD; Jane A. Cauley, DrPH; JoAnn E. Manson, MD, DrPH; Zhao Chen, PhDProton Pump Inhibitor Use, Hip Fracture,and Change in Bone Mineral Densityin Postmenopausal Women.Arch Intern Med. 2010;170;Author Affiliations: School of Pharmacy, University of Washington, Seattle (Dr Gray); Women’s Health InitiativeClinical Coordinating Center, Fred Hutchinson Cancer Research Center, Seattle (Dr LaCroix and Mr Larson); Department of Internal Medicine, University of California at Davis School of Medicine, Sacramento (Dr Robbins); Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Cauley); Division of Preventive Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts (Dr Manson); and Division of Epidemiology and Biostatistics, University of Arizona, Tucson (Dr Chen).
4IntroductionProton Pump Inhibitors (PPIs) are potent gastric acid suppressing medications, with millions of PPI prescriptions dispensed annually throughout the world for the treatment GERD.The effectiveness of PPIs to alleviate symptoms of heartburn and heal esophagitis have lead to the common practice of prescribing PPIs indefinitely for this chronic disorder.Recent large epidemiologic studies have suggested PPIs potent acid suppression may have a deleterious affect on calcium absorption and bone fracture risk.Yang YX, et al. Long-term PPI therapy and risk of hip fracture. JAMA. 2006;296: Targownik LE, et al. Use of PPIs and risk of osteoporosis-related fractures. CMAJ. 2008;179 : Yu EW, et al. Acid-suppressive medications and risk of bone loss and fracture in older adults. Calcif Tissue Int. 2008;83 :
5IntroductionThe FDA has recently issued a Broad Safety Communication to Patients, Consumers and Healthcare Professionals: “Possible increased risk of fractures to the hip, wrist, and spine with the use of PPIs.”
6Gray SL, et al. Arch Intern Med. 2010;170;765-771. AimThe authors utilized the ethnically and racially diverse database from the Women’s Health Initiative (WHI) to provide a biological evaluation of fracture risk associated with PPIs among women.Langer RD, et al. The Women’s Health Initiative observational study: baseline characteristics of participants and reliability of baseline measures. Ann Epidemiol. 2003;13 suppl 1:S107-S121. Women’s Health Initiative Study Group. Design of the Women’s Health Initiative clinical trial and observational study. Control Clin Trials. 1998;19:
7Gray SL, et al. Arch Intern Med. 2010;170;765-771. Study Design: MethodsThe WHI includes women participants of a prospective Observational Study (OS) and Clinical trials (CTs) of hormone therapy, dietary modification and/or calcium and vitamin D supplementation.WHI-OS n = 93,676 womenWHI-CTs n = 68,132 womenWomen recruited from 40 clinical centers located across the United States from 1993 to 1998.The study included women enrolled to WHI-OC plus WHI-CTs (n = 161,808) who had no prior hip fracture.Follow-up for this report was through Sept 2005, mean yrs
8Study Design: Outcome Assessment Gray SL, et al. Arch Intern Med. 2010;170;Study Design: Outcome AssessmentFractureTotal fracturesExcept: rib, sternum, skull, fingers, toes, & cervicalSelf Reported FracturesSemi to Annual mail &/or telephone questionnairesHip fractures:Central review of radiology reportsFracture outcomes reported for:HipClinical spineForearmWrist
9Study Design: Outcome Assessment Gray SL, et al. Arch Intern Med. 2010;170;Study Design: Outcome AssessmentMeasurement of Bone Mass Density (BMD)BMD at total hip, P-A spine and total body measured at baseline in 3 centersN = 10,833 womenSites: Pennsylvania, Alabama, ArizonaBMD MeasurementDual-energy x-ray absorptiometry using Hologic QDR densitometer (Hologic Inc, Waltham, Mass)Missing data on BMD, PPI use, etcComplete analysisHip n = 6,696Spine n = 6,626Total body n = 6,677
10Study Design: Outcome Assessment Gray SL, et al. Arch Intern Med. 2010;170;Study Design: Outcome AssessmentPPI ExposureParticipants brought all current Rx medications to baseline and 3-yr visit.Clinic interviewers entered all Rx into the WHI database.Drugs in the PPI Class:esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazoleDrugs in the H2RA class:cimetidine, famotidine, nizatidine, and ranitidine.Duration of use 3 categories:< 1 year or 1-3 yrs or >3 yrs
11Study Design: Outcome Assessment Gray SL, et al. Arch Intern Med. 2010;170;Study Design: Outcome AssessmentCOVARIATESRace, ethnicity, history of fracture, smoking.Physical fx by 10 item Medical OutcomeBMISelf reported physical activity (hrs/wk)Psychoactive medicationRx: corticosteroid,HRT,bisphosphonateDietary Calcium and vitamin D by food history and supplements.
12Study Design: Methods Statistical Analysis Gray SL, et al. Arch Intern Med. 2010;170;Study Design: MethodsStatistical AnalysisΧ2 for categorical variables2-sample t test for continuous variablesSAS statistical software (V 9.1; SAS Institute Inc, Cary, North Carolina)Multivariate analysis used for participants with missing covariate data. Hazard ratios (HR) and corresponding 95% confidence intervals (CIs) for fractures among PPI and H2RA users vs. non-users were calculated from Cox proportional hazards survival models for each fracture outcome.Model 1 adjusted for age, race or ethnicityModel 2 adjusted for smoking, physical activity, family history of hip fracture, DM, corticosteroid use.
16Results: Demographics Gray SL, et al. Arch Intern Med. 2010;170;Results: DemographicsCharacteristicNon-PPI user(N = 148,394)PPI user(n = 3,396)H2RA user(n = 10,016)Corticosteroid use %0.72.92.0HRT never %44.535.337.2HRT prior %15.817.818.7HRT current %39.746.844.1Ca Supplement %22.419.421.7Vit D Supplement %43.73.6
17Results: Risk for Fracture According to PPI and H2RA Use at Baseline Gray SL, et al. Arch Intern Med. 2010;170;Results: Risk for Fracture According to PPI and H2RA Use at BaselineCharacteristicNon-PPI user(N = 119,804)PPI user(n = 2,731H2RA user(n = 7,952)Hip Fx N=1500Model 111.21( )1.24( )Model 21.00( )1.07( )Clinical Spine Fx N=23152.04( )1.30( )1.47( )1.02( )
18Results: Risk for Fracture According to PPI and H2RA Use at Baseline Gray SL, et al. Arch Intern Med. 2010;170;Results: Risk for Fracture According to PPI and H2RA Use at BaselineCharacteristicNon-PPI user(N = 119,804)PPI user(n = 2,731)H2RA user(n = 7,952)Forearm/wrist Fx N=4881Model 111.31( )1.07( )Model 21.26( )1.05( )Total Fx N=21,2471.44( )1.19( )1.25( )1.08( )
19Gray SL, et al. Arch Intern Med. 2010;170;765-771. Results: Adj HRs Related to Duration PPI Use to Incidence of Hip, Clinical Spine, Forearm, Wrist % Tot Fx.PPI Dur. Use (yr)No.HipClinical SpineForearm orWristTotalNon User127,7561< 1 yr12041.67(1.55(1.27( )1-3 yr12180.981.40( )0.92( )1.19( )> 3 yr3081.11( )1.45( )1.30(2008 Top 200 generic drugs by total prescriptions. Drug Topics website.
20Study Results: Cohort at Baseline n =161,806 3,396 (2.1%) using PPI Gray SL, et al. Arch Intern Med. 2010;170;Study Results:Cohort at Baseline n =161,8063, (2.1%) using PPI10, (6.2%) using H2RAPPI users more likely to be obese, have osteoporosis, history of fractures, DM, HRT, Psychoactive Rx, poorer physical function and poorer self reported health.
21Study Results: Fractures Gray SL, et al. Arch Intern Med. 2010;170;Study Results: Fractures1,005,126 person-years of follow up1,500 hip fractures4,881 forearm or wrist fractures2,315 clinical spine fractures21,247 total fractures occurredAnnualized rates for Hip fractures were:0.15% for nonusers and0.19% for PPI medication users.
22Study Results: Fractures Gray SL, et al. Arch Intern Med. 2010;170;Study Results: FracturesIn Adjusted Models of Fx Risk & PPI useHip fractures risk ≠ increased on PPI26% ↑ Forearm or wrist fractures on PPI47% ↑ Clinical spine fractures on PPI25% ↑ Total fractures occurred on PPINo association between H2RA use and hip, clinical spine, forearm, or wrist, but use assoc with minimal ↑ risk in total fractures.
23Δ BMD for Total HipGray SL, et al. Arch Intern Med. 2010;170;
24Δ BMD for Total SpineGray SL, et al. Arch Intern Med. 2010;170;
25Δ BMD for Total BodyGray SL, et al. Arch Intern Med. 2010;170;
26Gray SL, et al. Arch Intern Med. 2010;170;765-771. Study ConclusionsThis very large prospective population-based study of post-menopausal women, showed that PPI use was not significantly associated with increased hazard of incident hip fracture.↑ Hip fracture risk was NOT noted with longer duration of PPI use nor for subgroup analysis of women classified by age, BMI, current HRT, calcium intake, or history of non-hip fracture.
27Gray SL, et al. Arch Intern Med. 2010;170;765-771. Study ConclusionsHowever, this study did show that baseline PPI use was associated with an increased risk for other fracture outcomes:↑ risk clinical spine fracture ↑ 47%↑ risk forearm or wrist fracture ↑ 26%↑ total fractures ↑ 25%Interestingly, total fracture risk in this study cohort was not reduced by calcium supplementation.
28Reviewer Comments Gray, et al, have shown: Gray SL, et al. Arch Intern Med. 2010;170;Reviewer CommentsGray, et al, have shown:That non hip fractures among post menopausal women are increased. However, they do not explain reason for this fracture risk.Could it be the women in this study with chronic PPI use are more frequently obese, sedentary, depressed on psychoactive medications and these co-variables are the greater risk for increased non-hip bone fracture?
29Gray SL, et al. Arch Intern Med. 2010;170;765-771. Reviewer CommentsResults of this study and others are a stern reminder to prescribers of PPIs to have heightened awareness of bone health.Whether using lower doses of PPI for chronic GERD will mitigate risk for non-hip fractures will require further scrutiny and prospective study.
30Gray SL, et al. Arch Intern Med. 2010;170;765-771. Reviewer CommentsFuture studies are needed to determine if BMD should be monitored among chronic PPI users, or perhaps subgroups with additional risk factors for osteoporosis and bone fracture should receive counter therapy to avoid bone loss and increased fracture risk.
31Gray SL, et al. Arch Intern Med. 2010;170;765-771. Reviewer ConclusionsThe clinician is urged to remember that although the risk for bone fracture is increased among post menopausal women on chronic PPI. There may be many other co-founding variables that influence fracture risk. The reader is referred to Screening for Osteoporosis: An Update for the U.S. Preventive Services Task Force Ann Intern Med. 2010;153:The recent FDA Alert should remind all prescribers of PPIs to consider evaluation of “bone health” when indefinite PPI therapy is necessary.