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Safety of Long Term Usage of Proton Pump Inhibitors
with Focus on Bone Fracture Risks
Yunkyung Lee, Pharm.D.
PGY1 Community Pharmacy Resident
HEB Pharmacy/University of Texas
Preceptor: Roxann Soliz, R.Ph
Residency Director: Nathan D. Pope, Pharm.D.
Pharmacy Practice Rounds
January 13, 2012
Objectives:
1.
2.
3.
4.
Review current prevalence of Proton Pump Inhibitors (PPIs) usage
Define the FDA approved indications of PPIs
Discuss the concerns associated with long term PPI usage
Suggest the proper usage of PPIs
1
I. Introduction
A. Proton Pump Inhibitors (PPIs) are the most potent agents used for gastric acid suppression.1
B. Millions of PPI prescriptions are dispensed annually in the United States and worldwide. 1
i. PPIs are the third highest-selling class of drugs in the U.S. 2
i. 113 million PPI prescriptions were written in the U.S. in 2008. 2
ii. Nexium has the second highest retail sales among all drugs since 2005. 2
1. Sales total $4.8 billion in 2008.2
C. PPIs are commonly used for various gastric acid-related conditions
i. Gastroesophageal reflux disorder (GERD) 3*
ii. Gastric/duodenal ulcer
iii. Helicobacter pylori (H. pylori) eradication 4*
iv. Erosive esophagitis
v. Pyrosis (heartburn), dyspepsia (OTC)
vi. Zollinger-Ellison syndrome
vii. NSAID-induced ulcer prophylaxis (off-label use) 5*
viii. Stress gastritis prophylaxis (off-label use)
(* = Recommended in current guidelines)
D. Recent studies raised several concerns regarding the long term usage of PPI
i. Drug interaction between PPIs and clopidogrel (Plavix®)
ii. PPIs may decrease the absorption of calcium, vitamin B12, magnesium and iron
iii. Long term acid suppression may lead to the development of atrophic gastritis which
could be a precursor of cancer
iv. PPIs may be associated with a higher risk of infections
a. Pneumonia and Clostridium difficile (C. diff)
v. Patients on PPIs are at increased risk of fractures
II. Background
A. Eight PPIs are currently available on the market in the U.S.
i. Omeprazole (Prilosec®)
ii. Omeprazole/sodium biscarbonate (Zegerid®)
iii. Esomeprazole (Nexium®)
iv. Naproxen/esomeprazole (Vimovo®)
v. Lansoprazole (Prevacid®)
vi. Dexlansoprazole (Dexilant®)
vii. Rabeprazole (Aciphex®)
viii. Pantoprazole (Protonix®)
B. Mechanism of action
i. PPIs reduce acid production by irreversibly inactivating gastric H+/K+-ATPase (proton
pump) of parietal cells6-8
a. PPIs can suppress daily acid production by 80-95%
b. PPIs provide prolonged acid suppression (24-48 hours) as acid secretion resumes
only after new pump molecules are synthesized
C. Pharmacokinetics
i.
PPIs are prodrugs that require acidic environment in order to be activated.
ii.
PPIs are extensively metabolized by CYP2C19 and 3A4
D. Drug interactions
i.
All PPIs except pantoprazole prolong the elimination of warfarin
ii.
Esomeprazole and omeprazole interfere with the clearance of diazepam
iii.
Omeprazole decreases clearance of phenytoin
2
Omeprazole competes with clopidogrel (Plavix®) for 2C19
a. Clopidogrel is a prodrug and activated by 2C19. Omeprazole decreases the
efficacy of clopidogrel by inhibiting 2C19. Pantoprazole is less likely to result in
this interaction.
b. FDA recommends avoiding concurrent use of clopidogrel and omeprazole (both
OTC and prescription dose)
1. Separating the dose of two medications will not reduce drug interaction.
2. Esomeprazole should not be used with clopidogrel either.
E. Chronic use of PPIs and the risk of gastric cancer
i.
Hypergastrinemia (gastrin levels of >500 ng/L)6
a. Acid suppression leads to increased levels of gastrin in most patients
b. Gastrin stimulates gastric acid secretion
1. By directly binding to its specific receptor on parietal cells
2. By indirectly stimulating histamine release from enterochromaffin-like
cells
c. In rats, prolonged suppression of acid secretion resulted in enterochromaffin-like
cells hyperplasia and carcinoids
d. In humans, enterochromaffin-like cells hyperplasia is present in 10-30% of
patients. Nonetheless, gastric carcinoids have never been seen in long term PPI
users.
1. Enterochromaffin-like cells constitute 35% of human gastric endocrine
cells population (compared to 65% in rats)
e. Long-term PPI use is not a risk factor for the development of enterochromaffinlike cells neoplasm.
f. Hypergastrinemia ccurs in ~5-10% of chronic omeprazole users
g. This condition may predispose to rebound hypersecretion of gastric acid upon
discontinuation of therapy
ii.
H. pylori positive patients on long term PPI treatment 6
a. H. pylori has been classified as a carcinogen by World Health Organisation
b. The persistent inflammation caused by H. pylori may lead to the development of
atrophic gastritis and intestinal metaplasia, conditions at increased risk of gastric
cancer.
c. H. pylori usually colonizes the antral mucus layer causing an antral predominant
gastritis; in these cases intestinal metaplasia is rare and the risk of cancer is low
iv.
(Figure 3) Anatomy of the stomach
Source: histopathology-india.net
3
d. When acid secretion is impaired, H. pylori colonizes the body of the stomach
determining a corpus predominant gastritis
e. Studies confirmed a progression toward atrophic gastritis in H. pylori positive
patients on long term omeprazole, compared to no risk in H. pylori negative
patients.9,10
f. Even though corpus gastritis and gastric atrophy are major risk factors for the
development of adenocarcinoma, there is no study demonstrated an increased
risk of gastric cancer in H. pylori positive patients on long term PPI treatment.
F. Chronic use of PPIs and the risk of GI infections6
i.
The GI tract has three different defense mechanisms: integrity of the membranes and
mucous layer, GI microflora, and gastric acidity
ii.
Diarrhea is the most common adverse event with long term PPI use (3.7-4.1%)
iii.
Pathogens found in patients are Salmonella, Campylobacter and C. diff
a. Salmonella and Campylobacter are acid sensitive microorganisms11-13
b. C. Diff produces acid-resistant spores which are its main vehicle of transmission.
However, at its vegetative phase it is very acid sensitive.17
c. Higher incidence of Campylobacter infections in patients treated with PPI has
been observed in three studies (OR 1.7-11.7) 11-13
1. PPI use longer than one month prior to infection determines a ten-fold
increase in the risk of developing Campylobacter related diarrhea
d. Similarly, the correlation between Salmonella infection and gastric acid
suppression has been demonstrated in four case-control studies (OR 2.6-11.2)12-16
e. Cunningham et al conducted a retrospective case-control study and found that,
apart from antibiotics, PPI use within the preceding two months constituted an
additional risk factor for C. Diff diarrhea in hospitalized patients (OR 2.5; 95%
Cl 1.5–4.2).17
iv.
Therefore, in hospitalized patients with concomitant risk factors and multiple
concomitant treatments, PPI may contribute to bacterial colonization by reducing GI
defense, but prospective studies are needed to evaluate the real risk related to PPI use.
G. Chronic use of PPIs and the risk of pneumonia6
i.
The stomach is normally free of bacteria due to its acidity. Acid suppressive therapy may
cause bacterial overgrowth in the upper GI tract and gastric colonization by
microorganisms.
ii.
This condition may predispose mechanically ventilated patients to the development of
pneumonia.
ii.
Three studies have investigated the risk of pneumonia with PPIs
Laheij et al
(2004) 18
•
•
Gulmez et al
(2007) 19
•
•
•
Gulmez et al
•
Large cohort study (n=364 683) evaluated the impact of PPI use on
the development of community-acquired pneumonia (CAP)
People who are on PPI or H2-blocker were at four-fold higher risk of
developing pneumonia compared to non-users (incidence rates 2.45
vs. 0.6 per 100 person-year)
Positive correlation between the PPI dose and risk was observed.
Population-based case-control study on hospitalized patients who
developed CAP during a four year period
These case patients (n=7642) were compared with controls
(n=34176) matched for sex and age
The association between the current use of PPI and the frequency of
4
(2007) 19
(Cont’)
Eom et al
(2011) 20
•
•
•
iii.
pneumonia had an OR of 1.5 (95% CI 1.3–1.7)
No significant association was found with H2 blocker or past use of
PPI. No dose-response relationship was observed.
Meta-analysis to summarize the association between acid
suppressive medications and pneumonia (both CAP and HAP)
Eight observational studies showed that risk of pneumonia was
higher among PPI users (OR 1.27, 95% CI 1.11-1.46)
Therefore, usage of PPI was found to be associated with an increased incidence of
pneumonia. Therefore, clinicians should be cautious when prescribing PPIs for patients at
high risk of developing pneumonia
H. Chronic treatment with PPIs decrease absorption of cyanocobalamine (vitamin B12) 6,7
i. Physiology 6
a. Gastric acid and pepsin are essential in order to release cobalamine (precursor of
vitamin B12) from dietary proteins.
b. Once released, free cobalamin binds to R-protein secreted from the parietal and
salivary cells.
c. In the duodenum, pancreatic enzymes cleave the R-protein–cobalamin complexes
and free cobalamin binds to the intrinsic factor secreted from gastric parietal
cells.
d. Finally, the cobalamin-intrinsic factor complex is absorbed in the ileum.
(Figure 2) Physiology of vitamin B12 absorption
Mouth
Unbound B12 may
be absorbed under
the tongue
→
Stomach
• Enzymes and acid
cause protein-bound B12
to detach from protein
• R-protein picks up B12
• IF secreted
→
Duodenum
• R-protein releases B12
• IF picks up B12
Ileum
IF-B12 attaches to IF-B12receptor on intestine cell
Source: http://www.veganhealth.org/b12/dig
ii. The decrease of gastric acidity may prevent the release of vitamin B12 from dietary
proteins.6
iii. Different studies that have investigated whether long term PPI therapy cause vitamin B12
malabsorption.
Marcuard et al • Evaluated vitamin B12 absorption before and after a short term
(1994) 21
omeprazole therapy
• Ten healthy male volunteers (age range 22–50 years)
• Each participant served as his own control
• Five participants were randomized to receive omeprazole 20mg
and the other five received 40 mg daily for two weeks
• Vitamin B12 absorption decreased from 3.2% to 0.9% (P =0.031)
in omeprazole 20mg group
• Vitamin B12 absorption decreased from 3.4% to 0.4% (P< 0.05) in
omeprazole 40mg group
Force et al
• Retrospective case-control study to evaluate the relation between
(2003) 22
long term acid suppression and the need of vitamin B12
5
•
•
•
•
Dharmarajan
et al (2008) 23
•
•
supplement
Patients were selected from a large Medicaid database
(n=109 844) between 1995 and 1997
Case patients (n=125) were defined as those who required a first
vitamin B12 injection during the study period
Four control patients were age and gender matched to each case
23 patients (18.4%) had been exposed to chronic acid suppression
therapy compared with 55 (11.0%) of the control group (n=500)
(p = 0.025; OR 1.82; 95% CI 1.08–3.09)
Retrospective study with geriatric patients (n=659)
PPI use (duration averaged 18.2 months, SD ±16.0) was
associated with decreased serum B12 levels (P < .00005)
iv. Therefore, chronic use of PPIs is associated with decreased vitamin B12 absorption and
serum levels, especially in the aged population.
I.
Chronic treatment with PPIs decrease the absorption of magnesium6,7
i. Magnesium homeostasis is maintained by the balance of intestinal absorption and renal
excretion. Several genes and complex transport systems have been shown to be involved
in renal and intestinal magnesium transport, including TRPM6 and TRPM7, channels
conducting divalent cations (calcium and magnesium) into cells. These channels are
regulated by several factors including external protons, thus the increase of gastric pH
might influence the activity of such channels in some subjects.
ii. Multiple studies revealed the association between chronic PPIs use and
hypomagnesemia.24
a. Mackay et al reviewed 10 cases and found the following results.24
1. Average duration of PPI usage was 8.3 years
2. Patients presented with severe symptomatic hypomagnesemia with
significant morbidities (fatigue, unsteadiness, tetany, seizures, cardiac
arrhythmias and hospitalizations)
b. Sometimes hypomagnesemia is accompanied by hypokalemia and/or
hypercalcemia.24,25
c. The hypomagnesemia resolved when the PPI therapy was discontinued and
recurred if the PPI therapy was resumed.24,26,27
d. The hypomagnesemia was not resolved when the patient switched to different
PPI, thus it is a generic problem within the class.25
iii. Therefore, the use of PPI should be considered in the differential diagnosis of
hypomagnesemia.6
J. PPIs decrease the absorption of iron
i. Absorption of iron is affected by gastric acidity7
a. Gastric acid greatly improve the absorption of non-heme iron (66% of dietary
iron) by dissociating the iron salts from the food source and helping them to be
reduced to the ferrous state, so it can bind to ascorbate, sugars and amines to be
absorbed.
b. It is already known that iron-deficiency anemia results from conditions with low
or no gastric acid such as atrophic gastritis, pernicious anemia or gastric
resections.
Sharma et al
• Presented two cases showing how omeprazole impairs
28
(2004)
optimal absorption of oral iron supplement in patients
with iron-deficiency anemia
6
Once omeprazole was discontinued, hemoglobin and
MCV levels improved in both patients after 2 months
Hutchinson et al
• Found that seven patient with hereditary
(2007) 29
hemochromatosis on long term PPI treatment required
less number of maintenance phlebotomy
• Also found the absorption of dietary non-heme iron was
significantly reduced after 7 day PPI exposure in 14
hemochoromatosis patients with normal baseline iron
c. Relatively few studies have been done assessing the relationship between chronic
PPIs and iron absorption. Concurrent PPIs and oral iron supplements may cause
malabsorption of iron, thus close monitoring is warranted.
•
K. Chronic treatment with PPIs may decrease the absorption of calcium6,8,30
i. Gastric acid is an important mediator for calcium absorption in small intestine.6
ii. As calcium absorption is affected by several other factors beside gastric pH, studies on
the effects of PPIs on calcium absorption show conflicting results.1
iii. Several in vitro and animal studies suggested that PPIs may reduce bone resorption by
inhibiting H+/K+-ATPase on osteoclasts1,8
a. Bone resorption is a necessary process of normal bone metabolism
(Figure 3) Bone Metabolism
Source: Valsamis et al. Nutrition & Metabolism 2006 3:36
iv. Mechanism by which chronic PPI use may increase fracture is not clear yet, but
suggested possible mechanisms are:
a. Without appropriate acid environment, calcium may be retained in food reducing
its absorption.6,8
b. Reduced calcium absorption may lead to compensatory secondary
hyperparathyroidism which may increase the rate of osteoclastic bone resorption8
c. If PPIs inhibit the resorptive activity of osteoclasts, old bone cannot be replaced,
predisposing patients to fractures8
d. Gastric parietal cells seemed to have a potent endocrine role in estrogen secretion.
Atrophy of gastric mucosa seen in H. pylori positive patients reduces the number
of parietal cells leading to decreased local estrogen secretion.
1. Estrogen increases bone formation by osteoblasts
7
III. Studies
Objective
Design
Methods
Statistical
Analysis
Results
Yang, et al. Long-term proton pump inhibitor therapy and risk of hip fracture.
JAMA 2006;296:2947–2953.31
• To determine the association between PPI therapy and the risk of hip fracture
• Nested case-control study done in U.K using the General Practice Research Database
from 1987 to 2003
• Primary nested case-control analysis was done within the study cohort including all
people who use any PPI and those who do not use any acid suppression drug
• Secondary nested case-control analysis was done with H2 Receptor Antagonists
(H2RA) for comparison
• Exclusion criteria:
o Less than 365 days of total up-to-standard database follow up
o Age < 50 at the time of database enrollment
o Documented hip fracture prior to or during the first year of database follow up
o Received H2RA or PPI only during the non-up-to-standard periods of database
follow-up
• Cases defined as those with the first incident of hip fracture at least 1 year after the
initiation of the follow up
• Each case was matched with ten controls for sex, index date, year of birth, and both
calendar period and duration of up-to-standard follow-up before the index date
• Primary exposure: PPI therapy for longer than 1 year prior to the index date
• Primary outcome measure was the risk of hip fractures associated with PPI use
• Conditional logistic regression was used to calculate the unadjusted and adjusted ORs
and 95% CI
• P < 0.5 was considered statistically significant
• Examined potential confounders including risk factors for falling and osteoporosis,
comorbidity status (e.g. BMI, smoking history, dementia, anxiolytics,
bisphosphonates, etc.)
• Sex-specific risks was evaluated
• 10 834 hip fractures were identified among nonusers and 2722 incidents among PPI
users. (= 13 556 cases)
• Case group was matched with 135 386 controls.
• Incidence rate was 4 per 1000 person-years of PPI therapy while 1.8 per 1000 personyears among nonusers
• Cases were more likely to have medications or diagnoses associated with falling or
osteoporosis
• Adjusted OR for hip fracture on PPI > 1 year was 1.44 (95% CI 1.30-1.59; P<0.001)
• AOR for hip fracture on H2RA alone > 1 year was 1.23
• AOR for hip fracture on PPI alone > 1 year was 1.62
• When compared long term PPI to H2RA, AOR was 1.34
• Positive correlation exists between the duration of PPI and risk of fracture (Table 1)
(Table 1) Results
(cont’)
8
•
Hip fracture risk was significantly increased with higher PPI dose (Table 2)
(Table 2) •
Authors’
Conclusion
Strengths
Weaknesses
•
•
•
•
•
•
•
•
The risk of hip fracture associated with long term PPI was significantly higher in men
vs. women (OR 1.78 vs. 1.36; P=0.4)
Long term PPI therapy is associated with significantly increased risk of hip fracture
and the highest risk was observed in patients with high dose PPI
One of the first studies investigated this topic
Large sample size
Long follow up period
Multiple confounders were taken into consideration
Duration of exposure could have been underestimated as the information on PPI use
prior to the enrollment was not available
OTC calcium supplement use was not included in the study analysis
More women were on calcium supplement compared to men and this could have
skewed the result of sex-specific risks.
Targownik, et al. Use of proton pump inhibitors and risk of osteoporosis-related fractures.
CMAJ 2008;179:319–326.30
Objective
• To examine the effects of longer duration of PPI use on the development of
osteoporosis-related fractures
Design
• Retrospective matched cohort study done in Manitoba, Canada using Population
Health Research Data Repository
Methods
• Cases were defined as those aged 50 years and older with diagnosed vertebral or hip
fracture between 1996 and 2004
• Each case was matched to 3 controls with no history of hip, vertebral or wrist
fractures for age, sex, ethnic background and degree of comorbidity
• Exclusion criteria:
o People who had used osteoprotective medications in the year prior to the event
o Residents of long-term care facilities
• Inclusion criterion:
o Continuous residents of Manitoba between 1988 and 2004 to ensure follow-up
Methods
• Information on patients’ PPI exposure was obtained using Drug Program Information
(cont’)
Network database
o Information on other medications might have affected bone metabolism or the
risk of falls was also obtained
• Primary outcome was occurrence of an osteoporotic fracture
Statistical
• Baseline characteristics and usage of PPIs between cases and controls were compared
Analysis
using X2 test
9
•
•
•
•
Results
•
•
P value <0.05 was considered statistically significant
Patients with no prior exposure to PPIs or H2 blockers served as a reference group
Used conditional logistic regression models to calculate adjusted OR and 95% CI
Confounding variables are area of residence, income quintile, presence of
comorbidity, use of home care services and use of medication might have affected
risk of osteoporosis or fractures
OR was considered statistically significant if range of 95% CI did not include 1.0
15 792 cases were matched with 47 289 controls
(figure 4) Continuous PPI exposure and the risk of any type of fractures
•
No significant association between use of PPIs for 1-6 years and the development of
any fracture (hip, wrist or spine)
(figure 5) Continuous PPI exposure and the risk of hip fractures
Results
(cont’)
Authors’
Conclusion
Strengths
•
•
•
•
•
•
However, significant association was found between continuous PPI use for 7 years
and longer and any type of fracture (adjusted OR 1.92; 95% CI 1.16-3.18)
Risk of hip fracture increased with longer duration of PPI use
Long-term use of PPIs (especially for 7 or more years) is associated with increased
risk of fractures
Large population-based study
Studied patients with long duration of PPI use
Confirmed that the risk of fracture increases with the duration of PPI exposure
10
Weaknesses
•
•
•
•
Inability to track use of OTC calcium and vitamin D supplements; weight and BMI;
tobacco and alcohol use
Possibility of presence of other confounders (observational study)
Possibility of underestimation of vertebral fractures that do not lead to physician’s
intervention
Unable to determine whether increased fracture risk from PPIs is associated with
reduced bone density
Gray, et al. Proton pump inhibitor use, hip fracture, and change in bone mineral density in
postmenopausal women: results from the Women’s Health Initiative.
Arch Intern Med 2010;170:765–771.1
Objective
• To determine the associations of PPI use with various fracture risks including hip,
clinical spine, forearm or wrists and total fractures as well as changes in 3-year total
hip, posterior-anterior spine and total body bone mineral density (BMD)
Design
• Prospective analysis of 161 806 postmenopausal women aged 50-79 years included
in Women’s Health Initiative (WHI) Observational Study (OS; n=93 675 women)
and Clinical Trials (CT; n=68 131 women) with a mean (SD) follow up of 7.8 (1.6)
years
Methods
• Women were recruited from 1993 to 1998 at 40 centers in the U.S.
• Exclusion criteria:
o Do not plan to reside in the area for at least 3 years
o Presence of complicating conditions including alcoholism, drug dependency or
dementia
• Total fractures were defined as all reported clinical fractures other than those of the
ribs, sternum, skull or face, fingers, toes, and cervical vertebrae.
• Hip fractures were confirmed by a central review of radiology reports in both cohorts
• Non-hip fractures were confirmed only in CT cohort
• Self-reported clinical fractures were collected once (WHI-OS) or twice a year (WHICT) either by mail or telephone questionnaires and reviewed by physicians
• Baseline BMD was obtained in 10 833 women at 3 centers
• Participants were asked to bring all current prescription medications to the baseline
and 3-year visit and reported duration of use for each medication
• PPI dose was not obtained
• Participants also reported information on covariates including race, history of
fracture, smoking history, physical function and activity, BMI and medications
associated with fall and osteoporosis.
Statistical
• Baseline characteristics were compared by X2 tests and 2-sample t tests.
Analysis
• Multivariate analyses were done for participants with no missing data (n=130 487)
• Hazard ratio and 95% CI were calculated from Cox proportional hazards survival
models
Statistical
• Women were continuously followed up until the incidence of fracture, death or end
Analysis
of follow-up
(cont’)
• Two different covariate adjustments were done. First one adjusted for age, race, BMI,
and inclusion to CT. Second one further adjusted for variables predictive of fractures
• PPI use was entered as time-dependent exposure to evaluate change in PPI use over
time
• Subgroup analyses were done for age, hormone replacement therapy use, BMI,
osteoporosis, prior non-hip fracture, calcium intake, and presence of ulcer or
heartburn
11
•
•
•
•
As a sensitivity analysis, separate analysis was done only using adjudicated fracture
data from CT cohort.
Multivariate linear regression methods were used to assess the association of baseline
BMD with any PPI use and duration of PPI use, as well 3-year changes in BMD.
3396 (2.1%) were PPI users, and 10 016 (6.2%) were only using H2 blocker
392 (11.5%) had used PPI > 3 years, 1520 (44.8%) for 1-3 years, and 1484 (43.7%)
used for < 1 year
Only omeprazole (n = 2875 [84.7%]) and lansoprazole (n = 521 [15.3%]) were used
PPI users were more likely to be obese; have osteoporosis, history of fractures,
poorer physical function and poor/fair self-reported health
1500 hip fractures, 4881 forearm or wrist fractures, 2315 clinical spine fractures and
21 247 total fractures occurred
Multivariate adjusted HR for current PPI use were 1.00 for hip fracture (95% CI
1.18-1.82); 1.47 for spine (95% CI 1.05-1.51); 1.26 for forearm or wrist fractures
(95% CI 1.05-1.51); 1.25 for total fractures (95% CI 1.15-1.36)
Use of PPIs associated with marginal effect on 3 year BMD change at hip (p=0.05),
but not any other sites
No consistent trend was observed for fracture risk with duration of PPI use
Significantly increased risk for total fractures with PPI use was observed in the age
groups < 70 years (HR, 1.31-1.52) compared to age group 70 to 79 years with HR of
1.05 (p=0.02)
PPI users without history of fracture were at significantly higher risk (HR, 1.32; 95%
CI 1.20-1.46) compared to PPI users with history of fracture (HR 1.04)
Use of PPIs was not associated with hip fractures, however, was associated with
increased risks of clinical spine, forearm or wrist, and total fractures in
postmenopausal women
Large prospective population-based study
Diversity of participants
Large number of fracture events
Adjudication of hip fractures
Availability of data on numerous confounders not available in past investigations
(including calcium intake)
Ability to assess associations with BMD and fracture in the same study
OTC PPI use was not included in the study analysis
Users of PPIs had more chronic health conditions (including osteoporosis) and risk
factors for fractures such as older age, history of non-hip fracture
Relatively low prevalence of PPI use in the study sample (particularly long-term PPI
use)
Inability account for PPIs used in the past that were no longer being taken at baseline
Lack of information on the dose of PPI medication
Reliance on self-report of non-hip clinical fractures in the OS cohort
No spine radiographs obtained
•
•
•
Eom, et al. Use of Acid-Suppressive Drugs and Risk of Fracture:
A Meta-analysis of Observational Studies
Ann Fam Med 2011;9:257-267.8
To investigate the association between the use of PPI or H2RAs and fracture risk
Meta-analysis of observational studies
Followed MOOSE (Meta-analysis of Observational Studies in Epidemiology)
•
•
Results
•
•
•
•
•
•
•
•
•
•
Authors’
Conclusion
•
Strengths
•
•
•
•
•
Weaknesses
•
•
•
•
Weaknesses
(cont’)
Objective
Design
Methods
12
•
•
•
Statistical
Analysis
•
•
•
•
Results
•
•
•
•
•
•
•
guidelines
Searched MEDLINE (PubMed), EMBASE and Cochrane Library (from inception to
12/2010 for all three) using common key words related to acid suppressing drugs
(ASDs) and fracture risks (no limit)
Inclusion criteria:
o RCTs, cohort, nested case-control, and case-control studies investigated the
association between the use of ASDs (PPIs or H2RAs) and fracture risk
Data extraction:
o Author’s last name, publication year, country where the study was performed,
study design, study period, type of outcome (fracture of hip, vertebrae, wrist or
any site), type of agent (PPI or H2RA), adjusted OR and RR with 95% CI,
number of covariates adjusted in the analysis, cases and controls with or without
exposure, and duration of exposure
Long-term use was defined as > 1 year before the index date
Quality assessment of included studies was done using Newcastle-Ottawa Scale
Main analyses were examining the association between the use of PPIs, H2RAs or
both and the risk of fractures using adjusted data
Subgroup analyses were done by type of study, quality of study, number of covariates
adjusted, type of agent, fracture outcome, medication dose and sex
Examined heterogeneity of results across studies with Higgins I2
Evaluated publication bias of the studies using Begg funnel plot and Egger test
No RTC was found, 5 case-control studies, 3 nested control studies and 3 cohort
studies were included for analysis
o Published between 1997 and 2011
o 6 studies evaluated both agents, 4 examined only PPIs and 1 studied only H2RA
PPI use was associated with significantly increased risk of any fracture (adjusted OR
1.29; 95% CI 1.18-1.4; I2 = 69.8%; n=10) (Figure 6 on the next page)
Subgroup analysis by outcome: risk of hip fracture and vertebral fracture were
significantly increased, however, there was no significant association between PPI
use and the risk of other fractures (Appendix 1)
Long-term PPI use was associated with significantly increased risks of both any type
of fracture and hip fractures (Appendix 1)
Both high and usual PPI dose were associated with increased risk of hip fracture
(Appendix 1)
(Figure 6) PPI use and the combined risk of any fractures
Results
(cont’)
13
Authors’
Conclusion
Strengths
Weaknesses
•
•
•
•
•
•
PPI use was associated with significantly increased fracture risk, whereas H2RA was
not.
First meta-analysis on the use of ASDs and fracture risk
Studied the type of fracture, PPI dose and duration of PPI use
Confirmed that the risk of fracture increases with the duration of PPI exposure
Potential for bias
Possibility of uncontrolled confounding
IV. Discussion
A. Large randomized controlled trial is necessary to confirm the results of observational studies
V. Summary
A. Chronic PPI use does not seem to be associated with gastric cancer
B. PPIs appear to be associated with increased risk of GI infections and pneumonia especially in
patients with concomitant risk factors such as hospitalization and multiple antibiotics
C. Chronic use of PPI is associated with decreased serum vitamin B12 levels, especially in the
aged population
D. Chronic PPI therapy may cause hypomagnesemia so it should be considered as a differential
diagnosis
E. Concurrent PPIs and oral iron supplement may cause malabsorption of iron, thus close
monitoring is warranted
F. Chronic PPI use is associated with increased risk of fractures
VI. Conclusions
14
A. Chronic PPI therapy should be prescribed with proper indication
i. H2RAs, dietary modification and other lifestyle changes should be tried prior to PPIs
for dyspepsia and frequent heartburn
ii. OTC PPIs should be used only up to 2 weeks not more than 3 times a year
iii. H. pylori testing should be done prior to initiation of chronic PPI therapy
iv. Prophylactic PPIs should be discontinued once the stressor is gone
B. Chronic PPI therapy should be used more carefully in high risk patients
i. Postmenopausal women, patients with osteoporosis, elderly patients and people at high
risk of fall
ii. People at high risk of getting pneumonia
iii. People with iron-deficiency anemia, vitamin B12 deficiency and hypomagnesemia
iv. It seems appropriate to do routine testing to monitor calcium, vitamin B12, magnesium
and iron levels in long term PPI users.
References
1. Gray SL, LaCroix AZ, Larson J, et al. Proton pump inhibitor use, hip fracture, and change in bone
mineral density in postmenopausal women: results from the Women’s Health Initiative. Arch Intern
Med 2010;170:765–771.
2. Consumer Reports Health Best Buy Drugs. Drugs to Treat Heartburn and Stomach Acid Reflux: The
Proton Pump Inhibitors. May 2010.
3. DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal
reflux disease. Am J Gastroenterol 2005;100:190–200.
4. Malfertheiner P, Megraud F, O’Morain C, et al. Current concepts in the management of Helicobacter
pylori infection: the Maastricht III Consensus Report. Gut 2007;56:772–81.
5. Lanza FL, Chan FK, Quigley EM. Guidelines for prevention of NSAID-related ulcer complications.
Am J Gastroenterol 2009;104:728–38.
6. Lodato F, Azzaroli F, Turco L, et al. Adverse Effects of Proton Pump Inhibitors. Best Practice &
Research Clinical Gastroenterology 24 (2010) 193–201.
7. Ito T and Jensen RT. Association of Long-term Proton Pump Inhibitor Therapy with Bone Fractures
and effects on Absorption of Calcium, Vitamin B12, Iron, and Magnesium. Curr Gastroenterol Rep.
2010 December; 12(6): 448–457.
8. Eom CS, Park SM, Myung SK, et al. Use of Acid-Suppressive Drugs and Risk of Fracture: A Metaanalysis of Observational Studies, Ann Fam Med 2011;9:257-267.
9. Kuipers EJ, Lundell L, Klinkenberg-Knol EC, et al. Atrophic gastritis and Helicobacter pylori
infection in patients with reflux esophagitis treated with omeprazole or fundoplication. N Engl J Med
1996;334:1018–22.
10. Lundell L, Havu N, Miettinen P, et al. Changes of gastric mucosal architecture during long-term
omeprazole therapy: results of a randomized clinical trial. Aliment Pharmacol Ther 2006;23:639–47.
11. Neal KR, Scott HM, Slack RC, et al. Omeprazole as a risk factor for campylobacter gastroenteritis:
case-control study. Bmj 1996;312:414–5.
12. Garcia Rodriguez LA, Ruigomez A. Gastric acid, acid-suppressing drugs, and bacterial gastroenteritis:
how much of a risk? Epidemiology 1997;8:571–4.
13. Doorduyn Y, Van PeltW, Siezen CL, et al. Novel insight in the association between salmonellosis or
campylobacteriosis and chronic illness, and the role of host genetics in susceptibility to these diseases.
Epidemiol Infect 2008;136:1225–34.
14. Neal KR, Briji SO, Slack RC, et al. Recent treatment with H2 antagonists and antibiotics and gastric
surgery as risk factors for Salmonella infection. Bmj 1994;308:176.
15
15. Doorduyn Y, Van Den Brandhof WE, Van Duynhoven YT, et al. Risk factors for Salmonella
Enteritidis and Typhimurium (DT104 and non-DT104) infections in The Netherlands: predominant
roles for raw eggs in Enteritidis and sandboxes in Typhimurium infections. Epidemiol Infect
2006;134:617–26.
16. Garcia Rodriguez LA, Ruigomez A, Panes J. Use of acid-suppressing drugs and the risk of bacterial
gastroenteritis. Clin Gastroenterol Hepatol 2007;5:1418–23.
17. Cunningham R, Dale B, Undy B, et al. Proton pump inhibitors as a risk factor for Clostridium difficile
diarrhoea. J Hosp Infect 2003;54:243–5.
18. Laheij RJ, Sturkenboom MC, Hassing RJ, et al. Risk of community-acquired pneumonia and use of
gastric acidsuppressive drugs. Jama 2004;292:1955–60.
19. Gulmez SE, Holm A, Frederiksen H, et al. Use of proton pump inhibitors and the risk of communityacquired pneumonia: a population-based case-control study. Arch Intern Med 2007;167:950–5.
20. Eom CS, Jeon CY, Lim JW, et al. Use of acid-suppressive drugs and risk of pneumonia: a systematic
review and meta-analysis. CMAJ. 2011 Feb 22;183(3):310-9.
21. Marcuard SP, Albernaz L, Khazanie PG. Omeprazole therapy causes malabsorption of
cyanocobalamin (vitamin B12). Ann Intern Med 1994;120:211–5.
22. Force RW, Meeker AD, Cady PS, et al. Ambulatory care increased vitamin B12 requirement
associated with chronic acid suppression therapy. Ann Pharmacother 2003;37:490–3.
23. Dharmarajan TS, Kanagala MR, Murakonda P, et al. Do acid-lowering agents affect vitamin B12
status in older adults? J Am Med Dir Assoc 2008;9:162–7.
24. Mackay JD, Bladon PT. Hypomagnesaemia due to proton-pump inhibitor therapy: a clinical case
series. QJM 2010;103:387–395.
25. Hoorn EJ, van der Hoek J, de Man RA, et al. A Case Series of Proton Pump Inhibitor-Induced
Hypomagnesemia. Am J Kidney Dis. 2010
26. Epstein M, McGrath S, Law F. Proton-pump inhibitors and hypomagnesemic hypoparathyroidism. N
Engl J Med 2006;355:1834–1836.
27. Cundy T, Dissanayake A. Severe hypomagnesaemia in long-term users of proton-pump inhibitors.
Clin Endocrinol (Oxf) 2008;69:338–341.
28. Sharma VR, Brannon MA, Carloss EA. Effect of omeprazole on oral iron replacement in patients with
iron deficiency anemia. South Med J 2004;97:887–889.
29. Hutchinson C, Geissler CA, Powell JJ, Bomford A. Proton pump inhibitors suppress absorption of
dietary non-haem iron in hereditary haemochromatosis. Gut 2007;56:1291–1295.
30. Targownik LE, Lix LM, Metge CJ, et al. Use of proton pump inhibitors and risk of osteoporosisrelated fractures. CMAJ 2008;179:319–326.
31. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip
fracture. JAMA 2006;296:2947–2953.
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