Adverse Effects of Long-Term Proton Pump Inhibitor

Use: A Review for the Otolaryngologist

*D. Brandon Chapman, *Catherine J. Rees, *Dylan Lippert, †Robert T. Sataloff, and *S. Carter Wright, Jr.,
*Winston Salem, North Carolina and yPhiladelphia, Pennsylvania

Objective. Proton pump inhibitors (PPIs) are the mainstay of current medical management for laryngopharyngeal re-
flux, and treatment often involves long-term use of this class of medications. The long-term adverse effects of PPI use
have not been studied extensively, but several analyses have demonstrated epidemiological links between PPI use and
adverse outcomes. These include altered mineral and vitamin absorption, orthopedic injury, acute coronary syndromes
(ACS), and infectious risks.
Study Design. A PubMed search was performed for subject headings, including PPIs and adverse outcomes. Rele-
vant studies were included in this review. Studies were compiled, reviewed, and compared in a narrative form.
Results. Several epidemiological links between PPI use and metabolic, infectious, cardiac, and orthopedic adverse
outcomes were found. No definite causal effects were identified.
Conclusion. Given these epidemiological patterns, we recommend that the clinician be aware of these possible
unintended consequences. In addition, we recommend consideration of dual-energy X-ray absorptiometry (DEXA)
bone density scans in at-risk patients who have not been previously tested. We recommend consideration of vitamin
B12 and iron levels in selected patients who are at high risk. We also recommend close communication with our cardi-
ology colleagues, as we attempt to ascertain the relationship between clopidogrel and PPI use. We recommend caution
in the use of omeprazole in patients undergoing active treatment for ACS. Finally, we recommend consideration of
Helicobacter pylori or serum gastrin level testing in patients with known risk factors for gastric carcinoma.
Key Words: Reflux–Laryngopharyngeal reflux–Proton pump inhibitor–Antacid–Complications of proton pump
inhibitor.

INTRODUCTION Surgery recommended twice-daily dosing of PPIs for a mini-

Laryngopharyngeal reflux (LPR) has been well described in the
literature as a causative agent in a multitude of otolaryngologic
complaints, including hoarseness, globus pharyngeus, dyspha-
gia, sore throat, chronic cough, and other airway disorders.1 It
has been estimated that roughly 10% of patients presenting to
an otolaryngologist have an upper aerodigestive tract complaint
related to reflux.2
Although gastroesophageal reflux disease (GERD) and LPR
have been clearly shown to have different disease patterns,3
they are often treated with a similar basic approach. The tradi-
tional approach to GERD treatment involves a combination of
dietary/lifestyle modifications, acid suppression (via antacids,
histamine 2 receptor-antagonists [H2RAs], and/or proton
pump inhibitors [PPIs]). Once-daily dosing of PPIs may be
sufficient to treat GERD but fails to treat LPR in as many as
50% of LPR patients.3 As opposed to the physiological barriers
of the esophagus, the tissues of the larynx and pharynx have
little protection against gastric acid and pepsin exposure.4
This often necessitates around-the-clock aggressive PPI
therapy for treatment of LPR. A 2002 position statement by
the American Academy of Otolaryngology/Head and Neck
Accepted for publication October 29, 2009.
From the *Department of Otolaryngology, Center for Voice and Swallowing Disorders,
Wake Forest University Health Sciences, Winston Salem, North Carolina; and the
yDepartment of Otolaryngology—Head and Neck Surgery, Drexel University College of
Medicine, Philadelphia, Pennsylvania.
Address correspondence and reprint requests to Catherine J. Rees, Department of
Otolaryngology, Center for Voice and Swallowing Disorders, Wake Forest University
Health Sciences, Medical Center Boulevard, Winston Salem, NC 27157. E-mail:
crees@wfubmc.edu
Journal of Voice, Vol. 25, No. 2, pp. 236-240
0892-1997/$36.00
Ó 2011 The Voice Foundation
doi:10.1016/j.jvoice.2009.10.015
mum treatment period of 6 months for LPR.1
One dilemma is that PPIs were initially developed and mar-
keted primarily for the GERD patient. Once Koufman and
others brought LPR to our attention,5 this class of drugs was
an obvious choice, given their high efficacy and long duration
of action. Unfortunately, the long-term treatment and high dos-
ing that usually accompanies LPR treatment with PPIs has not
been extensively addressed, especially in the otolaryngology
literature. From the gastroenterology, cardiology, and general
medicine literature concerning epidemiological patterns associ-
ated with long-term PPI treatment emerged and received media
attention. These include abnormalities in vitamin and mineral
absorption, leading to increased risk factors for osteoporosis
and fractures. Other concerning patterns suggest an interference
with the function of platelet-inhibiting medications in cardiac
patients, increased risk of infection, and possibly even risks
of gastric carcinoma. This review article will attempt to bring
some of these issues to light in the otolaryngology literature.
OVERVIEW OF PROTON PUMP INHIBITORS
H2RAs have been suggested as one of the many first-line man-
agement options for mild LPR (those with symptoms that are
noticeable but do not impair the patient’s daily life signifi-
cantly).6 Although H2RAs have been shown to effectively in-
hibit gastric acid production, they have unfortunately been
shown to have two major limitations. This class of drugs has
a relatively short duration of action, suppressing gastric acid
for only 4–8 hours. Patients treated with this class of drugs
have also been shown to develop increased tolerance to the
drug within several weeks of treatment, decreasing their long-
term efficacy.6
D. Brandon Chapman, et al Adverse Effects of Long-Term PPI Use
As a class, PPIs are the most potent inhibitors of gastric acid
production.7 Once absorbed systemically, the reactive species
of PPIs irreversibly inhibits the H+K+-ATPase facing the lumen
of the secretory parietal cell in the gastric mucosa.8 Although
other acid-suppressing medications have been shown to have
decreased efficacy over time, PPI treatment is generally not lim-
ited by this, as they affect the final enzyme in the acid produc-
tion pathway.
In general, PPIs are considered relatively safe when com-
pared with many other prescription drugs. A recent study of
the short-term adverse effect reports related to esomeprazole
in the United Kingdom included almost 12 000 patients over
a period of 8 months (average length of treatment: 26 weeks).
During this time, 119 possible adverse effects were reported
by the prescribing physician probably or possibly related to
the medication. The most common adverse effects were nausea
and/or vomiting, diarrhea, dizziness, and headache. There were
few reported cases of hypersensitivity reaction, including three
cases of angioedema and two cases of anaphylaxis, which were
reported as possibly related to the medication.9 The goals and
aims of this study were more geared toward short-term
GERD treatment. With a mean treatment of 26 weeks, there
were no data examining the possible long-term effects of PPI
treatment.
Proton pump inhibitors and calcium
PPIs are believed to interfere with calcium absorption second-
ary to their induction of hypochlorhydria. Although most cal-
cium absorption takes place in the small intestine, most
dietary and supplementation forms of calcium must be dis-
solved and ionized from the food matrix or delivery form in
the stomach. This process is facilitated by gastric acid. Calcium
carbonate breakdown has been shown to decrease from 96% at
a pH of 1 to 23% at a pH of 6.1.10
O’Connell et al11 examined fractional calcium absorption in
a small group of women aged 65 years or older. They studied
the fractional absorption of radiolabeled calcium in 18 fasting
women in a randomized, crossover fashion. When compared
with placebo, omeprazole was found to decrease calcium
absorption efficiency in elderly women by an average 41%.
In another study, Graziani et al12 examined the effects of
omeprazole in calcium absorption in the short term. After
completing a 7-day low-calcium diet, the patients ingested
a test meal including 1 g of calcium. In patients taking a pla-
cebo, the postprandial calcium level rose significantly. In
patients who had ingested omeprazole, there was no significant
change in serum calcium levels. This would suggest that phys-
iological alterations in gastric pH might indeed inhibit calcium
absorption.
Elderly women are already more prone to osteoporosis, as the
body’s ability to absorb calcium decreases with age. This phys-
iological effect, combined with the possible contributions of
hypocalcemia related to PPIs, has led to concerns regarding
the adverse effects of osteoporosis, primarily hip fractures.
One of the body’s physiological responses to decreased calcium
absorption is to increase parathyroid hormone production
(secondary hyperparathyroidism). This results in increased
237
osteoclastic bone resorption, which would place the already
‘‘calcium-hungry’’ bones with even less structural support.
Hip fractures may be the most significant adverse outcome
related to osteoporosis. It is estimated that in excess of
350 000 hip fractures occur in the United States each year.
The mortality rate during the first year of life after a hip fracture
is 24%. There is also significant comorbidity associated with
hip fractures in the elderly, generally leading to a very poor
functional status postfracture. Only 60% of those suffering
a hip fracture will recover their prefracture walking ability by
6 months.13 Several recent population-based studies have eval-
uated hip fracture patients for an epidemiological link between
hip fractures and PPI use.
Yang et al14 conducted a well-designed nested case-control
study examining the risk of hip fractures related to the use of
PPIs. The adjusted odds ratio (AOR) for hip fracture associated
with more than 1 year of PPI use was 1.44. There was an even
more impressive risk of hip fracture in patients with a history of
long-term, high-dose PPI use (AOR: 2.65, 95% confidence in-
terval (CI): 1.80–3.90; P< 0.001). The study also demonstrated
a positive association with duration of therapy, as the strength of
association increased from 1.22 at 1 year to 1.41 at 2 years, 1.54
at 3 years, and 1.59 at 4 years. Finally, the study found a signif-
icant difference (P ¼ 0.04) when comparing long-term, PPI
therapy-associated risk of hip fracture in men versus women
(odds ratio [OR]: 1.78 vs 1.36, respectively). Although this is
counterintuitive, it may be secondary to one of the limitations
of the study, which was a difficulty capturing the use of calcium
supplementation (usually over the counter). One could surmise
that many female patients may have been on long-term calcium
supplementation that may have had a protective effect.
Although it is certainly impossible to exclude all confounding
variables, Yang et al, showed a very convincing epidemiologi-
cal link between PPI therapy and the risk of hip fractures.
Further studies that clearly delineate causality are still needed.
Targownik et al15 performed a case-control study assessing
cases of vertebral, wrist, or hip fractures in patients 50 years
or older. They assessed yearly intervals (years 1–7) of exposure
to PPI therapy and matched three age and comorbid controls for
each case. Specifically, hip fractures were significantly associ-
ated with PPI use after 5 or more years of use (OR: 1.62, 95%
CI: 1.02–2.58) and steadily increased with each additional year
of use. With regard to all three fracture sites, a significant asso-
ciation was only shown in patients with 7 or more years of con-
tinuous exposure to PPI (OR: 1.92, 95% CI: 1.16–3.18). Again,
causality was not shown, but this suggests an epidemiologic
link. However, similar to the article by Yang et al, this study
was limited by its ability to control for over-the-counter cal-
cium and vitamin D supplementation.
Proton pump inhibitors and vitamin B12 and iron
Because PPIs alter gastric pH, they can theoretically alter
absorption of certain nutrients. Dietary vitamin B12 requires
both gastric acid and pepsin to initiate the absorption process.
Valuck and Ruscin16 demonstrated a significant association
between vitamin B12 deficiency and the use of an H2 receptor
antagonist or PPI for 12 or more months (OR: 4.45, 95% CI:
238
1.47–13.34). However, most would agree that true vitamin B12
deficiency is unlikely if the patient is taking an adequate diet.17
Absorption of iron may also be altered by PPI use, as ferric iron
is reduced to ferrous iron, which is more soluble.17
Proton pump inhibitors and Clostridium difficile-
associated diarrhea
Although nosocomial Clostridium difficile-associated diarrhea
(CDAD) has been primarily linked with the use of antimicrobial
agents, recent observational reports have suggested a link with
the increased gastric pH caused by PPI therapy. It is believed
that the inhibition of gastric acidity limits the body’s defense
against ingested spores and bacteria. A 2008 study by Aseeri
et al18 investigated the relationship between CDAD in hospital-
ized patients and PPI use. In a retrospective case-control study,
the authors demonstrated CDAD associated with use of PPI in
hospitalized patients based on an OR of 3.6 (95% CI: 1.7–8.3,
P< 0.001). The OR was also increased to 2.14 in patients using
H2 receptor antagonists but was not significant, likely because
of the relatively small number of patients prescribed this class
of medication. This study was carefully controlled for environ-
mental factors (patient location in the hospital), antibiotic use,
and other comorbidities.
Proton pump inhibitors and pneumonias
PPI use has been linked to an increased risk of community-
acquired pneumonia (CAP). The proposed mechanism for this
phenomenon, similar to that of CDAD, is increased pathogenic
colonization of the upper aerodigestive tract because of less
gastric acid suppression. Sarkar et al19 conducted a nested
case-control study using the United Kingdom’s well-
established General Practice Research Database. The authors
noted a strong association with PPI therapy and CAP in the
short term (when PPI was started within 2, 7, or 14 days). Inter-
estingly, there was no increased risk in patients on longer-term
PPI therapy. These authors concluded that chronic PPI therapy
is not likely to be associated with increased risk of CAP. Gul-
mez et al20 found that recent (within 0–7 days) initiation of
PPI treatment was associated with an odds ratio of 5.0 (95%
CI: 2.1–11.7). They found the risk to decrease sharply with
the duration of therapy, with the OR for patients treated more
than 84 days to be 1.3 (95% CI: 1.2–1.4). They showed no
association with H2 receptor antagonists. Laheij et al21 demon-
strated an increased relative risk for CAP in patients currently
being treated with PPIs, with an adjusted relative risk of 1.89
(95% CI: 1.36–2.62). Current users of H2RAs also showed
a 1.63-fold increased risk of pneumonia (95% CI: 1.08–2.48).
There was a dose-related response in the PPI group, with cur-
rent PPI users using more than one defined daily dose, showing
a 2.3-fold increased risk of pneumonia compared with those
with past use of PPI. This dose-response finding was not corrob-
orated in the studies by Sarkar et al19 or Gulmez et al.20
Given the high prevalence of acid-suppressive medication
use in the inpatient setting, Herzig et al22 recently evaluated
inpatients for a link between PPI use and hospital-acquired
pneumonia (HAP). The authors studied all patients admitted
to their tertiary care hospital for at least 3 days over a period
Journal of Voice, Vol. 25, No. 2, 2011
of 3 years, excluding intensive care patients (to avoid inclusion
of ventilator-acquired pneumonia patients). Out of almost
64 000 admissions and over 42 000 unique patients, there
were 32 922 (52% of admissions) treated with acid-suppressive
medication. Most of them received PPIs (83%, compared with
23% treated with H2 receptor antagonists). The adjusted OR for
the group exposed to acid-suppressive medications was 1.3
(95% CI: 1.1–1.4). Further breaking down the HAP group
into aspiration pneumonia versus nonaspiration pneumonia,
the OR remained significant for both groups but stronger for
the aspiration pneumonia group (1.4 vs 1.2). Finally, a matched
propensity score analysis was used to control for confounding
variables. In this subset, only PPIs were associated with
a significant risk of HAP, whereas the risk with H2RAs was
not significant.
When evaluating these studies, it is important to understand
that PPI prescriptions are used as a surrogate for the presence of
reflux disease.22 This may not be appropriate, because reflux
disease that is asymptomatic or presents with atypical symp-
toms (such as cough) may not be treated. In other words, the
presence or absence of reflux disease is not well controlled
for in these studies. An improved evaluation would include con-
trols that have documented reflux disease, untreated with PPIs.
This would likely help delineate whether pneumonia is associ-
ated with untreated reflux or suppression of gastric acid by PPIs,
or neither.
Proton pump inhibitors and clopidogrel
Several observational studies have suggested an interaction
between omeprazole and clopidogrel, a platelet activation in-
hibitor used in acute coronary syndromes (ACS) and other ath-
erosclerotic disease processes. As clopidogrel often leads to
gastrointestinal bleeding, many cardiac and stroke patients
are placed on prophylactic PPI to reduce the risk of bleeding.
Clopidogrel inhibits platelet activation induced by adenosine
diphosphate (ADP). The prodrug of clopidogrel requires trans-
formation via the cytochrome P-450 system. This activity di-
rectly parallels the dephosphorylation of intraplatelet
vasodilator-stimulated phosphoprotein (VASP), making VASP
levels an accurate predictor of clopidogrel activity. In a dou-
ble-blind placebo-controlled trial, Gilard et al23 examined
124 consecutive patients undergoing coronary artery stent im-
plantation who were receiving aspirin and clopidogrel. Patients
were randomized to receive either omeprazole 20 mg/d or pla-
cebo for 7 days. Clopidogrel effect was evaluated with phos-
phylorated VASP levels in the form of a platelet reactivity
index (PRI). On day 7, patients in the PPI group had a signifi-
cantly higher PRI (51.4% compared with 39.8% on placebo,
P< 0.0001). The authors hypothesized that PPIs reduce the
biological action of clopidogrel, likely by competitive meta-
bolic effects on Cytochrome P450 2C19. Obviously, in condi-
tions, such as ACS, the goal is to have reduced platelet
activity, which appears to be inhibited by omeprazole.
In another retrospective series, Pezalla et al24 reviewed myo-
cardial infarction (MI) patients younger than 65 years, who
were determined to be adherent to clopidogrel therapy. They
stratified patients based on adherence to PPI use, finding
D. Brandon Chapman, et al Adverse Effects of Long-Term PPI Use
a difference in 1-year MI rates when comparing non-PPI users
and high PPI-exposure patients (3.08% vs 5.03%, respectively,
P< 0.05). After adjusting for comorbidities, they found the rel-
ative risk for MI in the high PPI use group to be 337% greater
than that in the non-PPI group. This study was limited by con-
founding risk factors and a lack of breakdown, with regard to
which specific PPIs were used.
Most recently, in a retrospective study of 8205 Veterans
Affairs patients, a multivariate analysis suggested that simulta-
neous use of clopidogrel and PPIs has the potential for adverse
cardiac effects. In this study, 63.9% of patients with ACS were
found to have been prescribed PPIs at discharge from the hospi-
tal in addition to clopidogrel. Most patients were treated with
omeprazole, with a smaller portion receiving rabeprazole. In
their analysis, Ho et al25 found that the use of clopidogrel +
PPI was associated with an increased risk of death or rehospital-
ization for ACS compared with that of clopidogrel without PPI
(AOR: 1.25, 95% CI: 1.11–1.41). Also, in patients taking clopi-
dogrel after hospital discharge and prescribed PPI at any point
during the follow-up period (3 years), a higher risk of death
or rehospitalization for ACS was found during the use of PPI
with clopidogrel (compared with that of clopidogrel without
PPI, giving an adjusted hazard ratio of 1.27). When evaluating
secondary outcomes, patients on PPI + clopidogrel were ulti-
mately found to have a higher risk of requiring revascularization
procedures compared with those taking clopidogrel alone
(15.5% vs 11.9%, respectively). In a nested case-control design,
patients were also found to have an increased risk of adverse
outcomes when taking clopidogrel + PPI (AOR: 1.32). Finally,
the authors showed that the use of PPI without clopidogrel was
not associated with death or rehospitalization for ACS among
patients not taking clopidogrel after discharge.
PPIs are metabolized by both CYP450 2C19 and 3A4, likely
in different proportions based on their isomeric forms. The ini-
tial concern regarding the aforementioned studies was that the
results suggested a class effect, or that all PPIs could alter clo-
pidogrel metabolism. On the contrary, several studies have sug-
gested that this is not likely to be an effect of the entire class of
PPIs. Pantoprazole does not appear to completely inhibit cyto-
chrome P450 2C19 and has not been linked to this adverse
effect on clopidogrel.26 A more recent study by Siller-Matula
et al17 found no statistical difference in platelet function
when comparing patients not on PPIs with those on either pan-
toprazole or esomeprazole. This suggests that patients being
treated with clopidogrel for acute MI may be best treated
with a PPI other than omeprazole. Clearly, more research com-
paring both the different PPIs and examining true outcome data
will help elucidate this important clinical question.
Proton pump inhibitors and atrophic gastritis
One final area of significant concern regarding long-term main-
tenance therapy with PPIs is their propensity to induce atrophic
gastritis. Theoretically, this could lead to an increased risk of
gastric cancer. One widely accepted model of gastric carcinoma
involves a stepwise progression from gastritis to atrophic gastri-
tis, to metaplasia, and eventually adenocarcinoma.7 In the pres-
ence of active Helicobacter pylori infection, this progression
239
appears to be even more rapid. Based on this, several large con-
sensus statements have suggested H. pylori testing and eradica-
tion in long-term PPI users.27 In addition, several studies28 have
suggested that long-term PPI use significantly increases the risk
of gastric fundic gland polyps, but most of these polyps appear
to have a low risk of dysplasia.
Prolonged PPI use can also lead to hypergastrinemia (excess
circulating gastrin hormone), as gastrin production by antral
G-cells is inhibited by low pH (thus uninhibited when PPIs
reduce acid production). Studies have demonstrated carcinoid tu-
mors of the gastric mucosa of rats associated with long-term PPI
use.29 Based on this concern, Freston recommended measuring se-
rum gastrin levels after 1 year of therapy. The U.S. Food and Drug
Administration (FDA) acknowledges that PPIs directly cause gas-
tric enterochromaffin-like cell hyperplasia in both animal and hu-
man models. To date, no evidence of neoplasia or dysplasia has
been noted in humans. However, the FDA states that ‘‘these studies
are of insufficient duration and size to rule out the possible influ-
ence of long-term administration of omeprazole on the develop-
ment of any premalignant or malignant conditions.’’30
Tamim et al31 conducted a nested case-control study over
a period of 8 years, examining patients with exposure to acid-
suppressive drugs (either H2 receptor antagonists or PPIs) for
long periods of time. Case patients were found to have a minor,
yet significant, increased risk of gastric carcinoma compared
with those not exposed to acid-suppressive drugs in the preced-
ing 5 years. One limitation in this study was the fact that gastric
carcinoma has a long latency period; hence, examining a longer
period of time might be necessary to discern any relationship
between acid suppression and gastric carcinoma.
A more recent study by Poulsen et al32 evaluated the associ-
ation between PPI use and gastric cancer in a large, population-
based registry. The incidence rate ratios (IRR) of gastric cancer
in patients taking either PPI or H2RA were 9.0 and 2.8, respec-
tively. In an effort to prevent bias in the form of reverse causality,
the authors further introduced a 1-year lag time for the date of
diagnosis of gastric cancer. In this subset, both PPI and H2RA
showed an IRR of 1.2 (95% CI: 0.8–2.0 and 0.8–1.8, respec-
tively). Directly comparing PPI with H2RA, there was an overall
IRR of 1.3 (95% CI: 0.7–2.3). There were also positive associ-
ations with longer follow-up and more prescriptions filled. By
including the 1-year lag time, the study was able to restrict for
many confounding variables. This study was limited by its abil-
ity to control for H. pylori infection as a confounding variable,
as only certain patients had undergone eradication therapy.
CONCLUSION
PPIs are an integral treatment modality in the management of
LPR, and therefore, the otolaryngologist must be aware of their
potential acute and chronic side effects. With more work being
published in both the general medical literature and the popular
press, we must be knowledgeable of the issues and controver-
sies surrounding these potentially life-threatening long-term
side effects of PPI use. As much of the data presented in the
review were epidemiological, there is little direct causal evi-
dence linking PPIs to the unintended consequences. As the
body of scientific data regarding long-term use of PPIs
240
continues to improve, we hope to either prove or disprove these
possible links. Until then, we recommend that the clinician be
acutely aware of these possibilities. In at-risk patients, it may
be appropriate to consider dual-energy X-ray absorptiometry
(DEXA) bone mineral density scans, vitamin B12 levels, and
iron levels. We also recommend close communication with
our cardiology colleagues as we attempt to ascertain the rela-
tionship between clopidogrel and PPI use. In addition, we rec-
ommend caution in the use of omeprazole in patients
undergoing active treatment for ACS. Finally, it may be prudent
to include H. pylori testing in the workup of LPR. As otolaryn-
gologists, we are prescribing PPIs to protect structures, such as
the pharynx, larynx, and esophagus, but we must keep in mind
that these medications have the potential for gastric effects, sys-
temic side effects, and medication interactions.
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