Transcript Literature Review

PPIs and Risk for Bone Fractures
http://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/UCM213307.pdf
Literature Review
Title: PPIs and Risk for Bone Fractures
Peter R. McNally, DO, FACP,
FACG
University Colorado Denver
School of Medicine
Center for Human Simulation
Aurora, 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
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 Initiative
Clinical 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).
Introduction
 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.
Introduction
 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/PostmarketDrugSafetyInformationforPatientsandProvid
ers/ucm213206.htm#SafetyAnnouncement#SafetyAnnouncement
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Aim
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.
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.
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Study 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
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Study 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
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Study Design: Outcome Assessment
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
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Study Design: Outcome Assessment
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
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Study Design: Outcome Assessment
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.
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Study 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.
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Results: Demographics
Characteristic
Non-PPI user
(N = 148,394)
PPI user
(n = 3,396)
H2RA user
(n = 10,016)
63.1
64.8
64.3
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
Age
BMI
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Results: Demographics
Characteristic
Non-PPI user
(N = 148,394)
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
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Results: Demographics
Characteristic
Non-PPI user
(N = 148,394)
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
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Results: Demographics
Characteristic
Non-PPI user
(N = 148,394)
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
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Results: Risk for Fracture According to PPI
and H2RA Use at Baseline
Characteristic
Non-PPI user
(N = 119,804)
PPI user
(n = 2,731
H2RA user
(n = 7,952)
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)
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)
Hip Fx N=1500
Clinical Spine Fx N=2315
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Results: Risk for Fracture According to PPI
and H2RA Use at Baseline
Characteristic
Non-PPI user
(N = 119,804)
PPI user
(n = 2,731)
H2RA user
(n = 7,952)
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)
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)
Forearm/wrist Fx N=4881
Total Fx N=21,247
Gray 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.
Hip
Clinical Spine
Forearm or
Wrist
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
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Study Results:
Cohort at Baseline n =161,806
 3,396
 10,016
(2.1%) using PPI
(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.
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Study Results: Fractures
1,005,126 person-years of follow up
 1,500 hip fractures
 4,881 forearm or wrist fractures
 2,315 clinical spine fractures
 21,247 total fractures occurred
 Annualized rates for Hip fractures were:
0.15% for nonusers and
► 0.19% for PPI medication users.
►
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Study Results: Fractures
In Adjusted Models of Fx Risk & PPI use
 Hip fractures risk ≠ increased on PPI
 26% ↑ Forearm or wrist fractures on PPI
 47% ↑ Clinical spine fractures on PPI
 25% ↑ 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 Hip
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Δ BMD for Total Spine
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Δ BMD for Total Body
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Study Conclusions
This very large prospective populationbased 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.
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Study Conclusions
However, this study did show that
baseline PPI use was associated with an
increased risk for other fracture
outcomes:
 ↑ risk clinical spine fracture
 ↑ risk forearm or wrist fracture
 ↑ total fractures
↑ 47%
↑ 26%
↑ 25%
Interestingly, total fracture risk in this
study cohort was not reduced by
calcium supplementation.
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Reviewer 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?
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Reviewer Comments
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.
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Reviewer Comments
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.
Gray SL, et al. Arch Intern Med. 2010;170;765-771.
Reviewer 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.