PPIs and Risk for Bone Fractures

PPIs and Risk for Bone FracturesPPIs and Risk for Bone Fractures

http://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/UCM213307.pdf

Literature ReviewTitle: PPIs and Risk for Bone Fractures

Literature ReviewTitle: PPIs and Risk for Bone Fractures

Peter R. McNally, DO, FACP, FACG

University Colorado Denver School of Medicine

Center for Human SimulationAurora, Colorado 80045

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, PhD

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, PhD

Proton Pump Inhibitor Use, Hip Fracture,

and Change in Bone Mineral Density

in Postmenopausal Women.

Arch Intern Med. 2010;170;765-771.

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).

IntroductionIntroduction Proton 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;296:2947-2953. Targownik LE, et al. Use of PPIs and risk of osteoporosis-related fractures. CMAJ. 2008;179 :319-326. Yu EW, et al. Acid-suppressive medications and risk of bone loss and fracture in older adults. Calcif Tissue Int. 2008;83 :251- 259.

IntroductionIntroduction

The 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.”

http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213206.htm#SafetyAnnouncement#SafetyAnnouncement

AimAim

The 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.

Gray SL, et al. Arch Intern Med. 2010;170;765-771.

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;19:61-109.

Study Design: MethodsStudy Design: Methods

The 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 women WHI-CTs n = 68,132 women Women 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 7.8 + 1.6 yrs


Study Design: Outcome AssessmentStudy Design: Outcome Assessment

Fracture Total fractures

Except: rib, sternum, skull, fingers, toes, & cervical

Self Reported Fractures Semi to Annual mail &/or telephone questionnaires

Hip fractures: Central review of radiology reports

Fracture outcomes reported for: Hip Clinical spine Forearm Wrist Total fractures



Measurement of Bone Mass Density (BMD) BMD at total hip, P-A spine and total

body measured at baseline in 3 centers N = 10,833 women Sites: Pennsylvania, Alabama, Arizona

BMD Measurement Dual-energy x-ray absorptiometry using Hologic QDR

densitometer (Hologic Inc, Waltham, Mass)

Missing data on BMD, PPI use, etc Complete analysis Hip n = 6,696 Spine n = 6,626 Total body n = 6,677



PPI Exposure Participants 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, rabeprazole

Drugs in the H2RA class: cimetidine, famotidine, nizatidine, and ranitidine.

Duration of use 3 categories: < 1 year or 1-3 yrs or >3 yrs



COVARIATES Race, ethnicity, history of fracture,

smoking. Physical fx by 10 item Medical Outcome BMI Self reported physical activity (hrs/wk) Psychoactive medication Rx: corticosteroid,HRT,bisphosphonate Dietary Calcium and vitamin D by food

history and supplements.


Study Design: MethodsStudy Design: Methods

Statistical Analysis Χ2 for categorical variables 2-sample t test for continuous variables SAS 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 ethnicity Model 2 adjusted for smoking, physical activity, family

history of hip fracture, DM, corticosteroid use.


Results: Demographics Results: Demographics


Characteristic Non-PPI user(N = 148,394)

PPI user(n = 3,396)

H2RA user(n = 10,016)

Age 63.1 64.8 64.3

BMI

Under Wt < 18.5 0.9% 0.3% 0.4%

Normal 18.5-24.9 35.1% 19% 22.6%

Over Wt 25-29.9 34.3% 36.2% 35%

Obese > 30 28.8% 43.6% 41.0%

Never Smoke 50.6 47.9 47.5

Past Smoke 41.2 45.3 44.6

Current Smoke 6.9 5.2 6.6




PPI user(n = 3,396)

H2RA user(n = 10,016)

White % 82.4 84 84

Black % 9 9 9.6

Hispanic % 4 4.1 3.6

American Indian % 0.4 0.5 0.5

Asian % 2.7 1.1 1.0

Unknown % 1.4 1.3 1.3

Functional Score>90 (%)

37.8 16.1 19.9

Parent broke hip % 12.8 13.4 12.6

Fair to Poor Health % 8.2 23.4 17.3




PPI user(n = 3,396)

H2RA user(n = 10,016)

DM % 4.3 7 6.2

MI % 5.9 15.3 12.7

Asthma/COPD % 9.5 19.4 15

Arthritis % 45.4 68.1 64.3

Osteoporosis % 7.2 14.8 10.6

PUD % 4.9 26.5 22.2

GERD > moderate % 7.1 30.9 34.1

Psych Rx % 9.4 27.3 21.4

Bisphosphonate Rx % 1.9 3.4 2.0




PPI user(n = 3,396)

H2RA user(n = 10,016)

Corticosteroid use % 0.7 2.9 2.0

HRT never % 44.5 35.3 37.2

HRT prior % 15.8 17.8 18.7

HRT current % 39.7 46.8 44.1

Ca Supplement % 22.4 19.4 21.7

Vit D Supplement % 4 3.7 3.6

Results: Risk for Fracture According to PPI and H2RA Use at Baseline




PPI user(n = 2,731

H2RA user(n = 7,952)

Hip Fx N=1500

Model 1 1 1.21(0.87-1.69)

1.24(1.02-1.50)

Model 2 1 1.00(0.71-1.40)

1.07(0.87-1.30)

Clinical Spine Fx N=2315

Model 1 1 2.04(1.65-2.51)

1.30(1.12-1.51)

Model 2 1 1.47(1.18-1.82)

1.02(0.87-1.20)





PPI user(n = 2,731)

H2RA user(n = 7,952)

Forearm/wrist Fx N=4881

Model 1 1 1.31(1.10-1.57)

1.07(0.95-1.20)

Model 2 1 1.26(1.05-1.51)

1.05(0.93-1.19)

Total Fx N=21,247

Model 1 1 1.44(1.32-1.56)

1.19(1.13-1.25)

Model 2 1 1.25(1.15-1.36)

1.08(1.02-1.14)

Results: Adj HRs Related to Duration PPI Use to Incidence of Hip, Clinical Spine, Forearm, Wrist % Tot Fx.

Results: Adj HRs Related to Duration PPI Use to Incidence of Hip, Clinical Spine, Forearm, Wrist % Tot Fx.


PPI Dur. Use (yr)

No. Hip Clinical Spine Forearm orWrist

Total

Non User 127,756 1 1 1 1

< 1 yr 1204 1 1.67 (1.22-2.27

1.55 (1.21-1.98

1.27 (1.13-1.44)

1-3 yr 1218 0.98 1.40 (1.02-1.92)

0.92 (0.67-1.26)

1.19 (1.05-1.35)

> 3 yr 308 1 1.11 (0.59-2.07)

1.45 (0.90-2.34)

1.30 (1.03-1.64

2008 Top 200 generic drugs by total prescriptions. Drug Topics website. Http://drugtopics.modernmedicine.com/drugtopics/data/articlesstandard/drugtopics/192009/597086/article.pdf

http://drugtopics.modernmedicine.com/drugtopics/data/articlesstandard/drugtopics/192009/597086/article.pdf

Study Results:Study Results:

Cohort at Baseline n =161,806

3,396 (2.1%) using PPI10,016 (6.2%) using H2RA

PPI users more likely to be obese, have osteoporosis, history of fractures, DM, HRT, Psychoactive Rx, poorer physical function and poorer self reported health.


Study Results: FracturesStudy Results: Fractures

1,005,126 person-years of follow up

1,500 hip fractures 4,881 forearm or wrist fractures 2,315 clinical spine fractures21,247 total fractures occurred

Annualized rates for Hip fractures were:► 0.15% for nonusers and ► 0.19% for PPI medication users.


Study Results: FracturesStudy Results: Fractures

In Adjusted Models of Fx Risk & PPI use

Hip fractures risk ≠ increased on PPI26% ↑ Forearm or wrist fractures on PPI47% ↑ Clinical spine fractures on PPI25% ↑ Total fractures occurred on PPI

No association between H2RA use and hip, clinical spine, forearm, or wrist, but use assoc with minimal ↑ risk in total fractures.


Δ BMD for Total HipΔ BMD for Total Hip


Δ BMD for Total SpineΔ BMD for Total Spine


Δ BMD for Total BodyΔ BMD for Total Body


Study ConclusionsStudy Conclusions

This 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.


Study ConclusionsStudy Conclusions

However, 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.


Reviewer CommentsReviewer Comments

Gray, et al, have shown:

1. 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?



2. Results of this study and others are a stern reminder to prescribers of PPIs to have heightened awareness of bone health.

3. Whether using lower doses of PPI for chronic GERD will mitigate risk for non-hip fractures will require further scrutiny and prospective study.



4. Future 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.


Reviewer ConclusionsReviewer Conclusions

The 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;153:99-111.

The recent FDA Alert should remind all prescribers of PPIs to consider evaluation of “bone health” when indefinite PPI therapy is necessary.


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PPIs and Risk for Bone Fractures