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Gastric and Duodenal Safety of Daily Alendronate
James G. Donahue, DVM, PhD;
K. Arnold Chan, MD, ScD;
Susan E. Andrade, ScD;
Arne Beck, PhD;
Myde Boles, PhD;
Diana S. M. Buist, PhD;
Vincent J. Carey, PhD;
Julie M. Chandler, PhD;
Gary A. Chase, PhD;
Bruce Ettinger, MD;
Paul Fishman, PhD;
Michael Goodman, PhD;
Harry A. Guess, MD, PhD;
Jerry H. Gurwitz, MD;
Andrea Z. LaCroix, PhD;
T. R. Levin, MD;
Richard Platt, MD, MS
Arch Intern Med. 2002;162:936-942.
ABSTRACT
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Background Isolated case reports of gastric ulcers after alendronate sodium use
raised concern about the gastroduodenal safety of daily alendronate. This
study was conducted to estimate the excess risk of hospitalizations for gastric
or duodenal perforations, ulcers, and bleeding associated with alendronate
use.
Participants and Methods Study subjects were 6432 men and women, 35 years or older. The subjects
were members of 8 health maintenance organizations who were dispensed alendronate
from October 1995 through September 1997. There was also a group of 33 176
age-, sex-, and health maintenance organization–matched unexposed persons.
Because of concerns that osteoporosis might confound the association between
alendronate use and perforation, ulcer, or bleeding, a second comparison group
of 9776 women, 60 years or older, who had osteoporotic fractures was assembled.
Hospitalizations for gastroduodenal events were identified by discharge diagnosis
codes in automated claims records, and confirmed by manual record review.
Results Based on the 14 confirmed events in the alendronate group and 35 in
the unexposed group, the crude incidence rate ratio of gastroduodenal perforation,
ulcer, or bleeding for the alendronate cohort was 3.0. The incidence rate
ratio was 1.8 (95% confidence interval, 0.8-3.9) after control for prior hospitalizations,
comorbidity, and recent exposure to prescription nonsteroidal anti-inflammatory
drugs and oral corticosteroids. The crude incidence ratio rate for the age,
sex, and health maintenance organizations–restricted cohort of alendronate
users relative to the fracture cohort was 1.1 and the adjusted incidence rate
ratio was 1.1 (95% confidence interval, 0.6-2.2).
Conclusions Osteoporosis and related factors appear to play an important role in
the relationship between alendronate use and confirmed gastroduodenal perforation,
ulcer, or bleeding; a substantial fraction of the increased risk we observed
for alendronate users in the unadjusted analysis was the result of confounding.
INTRODUCTION
TEN MILLION to 20 million postmenopausal women in the United States
have osteoporosis. The enormous medical, social, and economic consequences
are due primarily to osteoporotic fractures; in 1995 they were responsible
for at least 400 000 hospitalizations, 2.5 million physician visits,
and medical expenditures of nearly $14 billion.1-2
Several clinical trials have demonstrated the efficacy of alendronate sodium
to treat osteoporosis and prevent osteoporotic fractures.3-8
Although esophageal irritation was recognized as a potential side effect of
alendronate, reports to the Food and Drug Administration in 1996 and 1997
raised concern that alendronate may have previously unappreciated potential
for gastric and duodenal injury, especially among the elderly.9-11
This observational study was designed to compare the incidence of hospitalizations
for gastric or duodenal perforations, ulcers, and bleeding among users of
alendronate with that among a randomly selected, unexposed group. However,
osteoporosis (the condition for which alendronate is indicated) is associated
with excess nontrauma mortality12-14
and was therefore a potential confounder in the association between alendronate
use and gastrointestinal injury. Although the prevalence of osteoporosis among
the study population could not be directly measured, we sought to approximate
the magnitude of this potential confounding effect by comparing the rates
of gastroduodenal perforations, ulcers, and bleeding in a cohort of older
women who had nonpathologic fractures with age-matched women exposed to alendronate.
PARTICIPANTS AND METHODS
STUDY POPULATION
This was a retrospective cohort study of health plan members of 8 health
maintenance organizations (HMOs) in geographically diverse locations. The
institutional review board of each HMO approved the study protocol. Membership,
demographic, drug dispensing, and hospital discharge information were obtained
from automated databases at each HMO. Eligible subjects were continuously
enrolled in the HMO for at least 1 year after October 1, 1994 (1 year before
the initial marketing of alendronate), had prescription drug coverage during
the entire observation period, and had hospital records generally accessible
to study personnel. Three study cohorts (alendronate, unexposed, and fracture)
were identified.
The exposed cohort consisted of persons who were dispensed 10-mg tablets
of alendronate at least once from October 1995 through September 1997 and
were 35 years or older at the time of the first alendronate dispensing. Person-time
at risk for an individual started on the date alendronate was dispensed and
extended for a number of days equal to the number of tablets dispensed, according
to the recommended dose of 1 10-mg tablet per day. When dispensings overlapped,
the number of tablets dispensed in all such dispensings was summed and time
at risk was computed from the first dispensing date. Only the first 15 days
of a gap in dispensing were considered alendronate-exposed time. Person-time
at risk ended on whichever of the following occurred first: September 30,
1997; first hospitalization for confirmed esophageal, gastric or duodenal
perforations, ulcers, or bleeding; disenrollment; or the date that the last
dispensed alendronate pills were supposed to be taken, plus 15 days. Since
the 40- and 5-mg tablets were infrequently dispensed (52 and 65 persons, respectively),
individuals who were given these dosages were not included in the study.
The unexposed cohort was frequency matched to the alendronate cohort
with respect to age and sex at a ratio of 5:1 within each HMO. These individuals
were not given alendronate and person-time at risk for each was counted from
a randomly chosen referent date after October 1, 1995, to whichever the following
occurred first: September 30, 1997; first hospitalization for confirmed esophageal,
gastric, or duodenal perforations, ulcers, or bleeding; or disenrollment.
The fracture cohort was composed of women older than 60 years as of
October 1, 1994, judged to have a high prevalence of osteoporosis. They were
from 7 of the 8 participating HMOs, and had at least 1 diagnosis code between
October 1994 and September 1997 for fracture of the hip, humerus, distal tibia,
vertebrae, or wrist in ambulatory or hospital records. Women who had at least
1 diagnosis code that represented bone cancer, breast cancer, colon cancer,
lung cancer, cancer metastasis, multiple myeloma, concurrent major trauma,
or pathologic fracture were excluded. As part of a secondary analysis, the
fracture cohort was further subdivided into a hip fracture group and a nonhip
fracture group. Women who had multiple fractures, one being a hip fracture,
were classified as having hip fracture. Diagnosis codes for hip fracture have
been reported to have high predictive value positive rates.15
We reviewed medical records of a random sample of 404 women who fulfilled
the selection criteria for nonhip fractures to evaluate the accuracy of the
fracture identification algorithm. We calculated the proportion of true positives
for each nonhip anatomic site at each HMO and excluded cases of fracture sites
from HMOs that had a true-positive rate of less than 60%. Among the remaining
fracture groups reviewed, 314 (82%) of 383 women were confirmed to have a
nonpathologic fracture. Fracture-exposed person-time started on October 1,
1995, and continued until the earliest of September 30, 1997; disenrollment;
first dispensing of alendronate; or first hospitalization for confirmed esophageal,
gastric, or duodenal perforations, ulcers, or bleeding.
ASCERTAINMENT OF OUTCOMES
Persons with upper gastrointestinal events of interest were identified
in each HMO by a 3-step procedure: (1) computerized search of claims files;
(2) abstraction of hospital records; and (3) confirmation of perforations,
ulcers, or bleeding. Hospital claims files were searched with International Classification of Diseases, Ninth Revision, Clinical Modification codes from October 1995 through September 1997 for the discharge diagnoses
of gastric ulcer (531.xx), duodenal ulcer (532.xx), peptic ulcer (533.xx),
gastrojejunal ulcer (534.xx), gastrointestinal hemorrhage (578.xx), or esophageal
ulcer (530.2). Full-text hospital records from hospitalizations with any one
of these codes were reviewed to abstract additional information to confirm
or reject the diagnosis and to determine the time of onset of signs and symptoms
(before or after admission to the hospital). Three investigators (J.G.D.,
K.A.C., and R.P.) who were blinded to alendronate exposure status, reviewed
the anonymized abstraction forms. The second reviews were conducted for all
individuals except those for whom the primary review clearly indicated that
there was no perforation, ulcer, or bleeding. Final arbitration of the small
number of indeterminate records that remained was performed in a blinded manner
by a gastroenterologist (T.R.L.).
Persons were classified as cases if they were hospitalized for esophageal,
gastric, or duodenal ulcer as confirmed by surgery, endoscopy, radiology,
or autopsy. In addition, cases included persons with upper gastrointestinal
hemorrhage determined by surgery, endoscopy, radiology, or autopsy to originate
from esophageal, gastric, or duodenal ulcer; hemorrhagic gastritis; or duodenitis.
Excluded from both the case and comparison groups were persons with esophageal,
gastric, or duodenal events with onset during hospitalization or other specified
pathological conditions (eg, neoplasm). Cases of duodenal and pyloric ulcer
were classified as "duodenal ulcer." Cases of gastric, gastrojejunal, and
gastric or duodenal ulcer occurring simultaneously were classified as "gastric
ulcer."16 Persons with nonprimary esophageal
ulcers concurrent with gastric or duodenal ulcers were also classified by
either gastric or duodenal ulcer as noted above.
ADJUSTMENT FOR COMORBIDITY
Comorbidity was assessed through the chronic disease score, which is
based on age, sex, and dispensings of prescription drugs used to treat specific
chronic diseases during the previous 12 months.17-18
The scores are directly related to and predictive of utilization of health
care resources; higher scores reflect higher health care costs.17-19
DATA ANALYSIS
We used the method of Breslow to estimate the incidence rate ratios
(IRRs) and 95% confidence intervals (CIs).20
The protocol-defined primary analysis was to compare the incidence of gastric
or duodenal perforations, ulcers, and bleeding among the alendronate cohort,
the unexposed cohort, and the fracture cohort. Secondary analyses included
the evaluation of event rates among the hip and nonhip fracture groups and
comparisons with the age-sex-HMO–restricted alendronate cohort. The
impact of potential effect modification and confounding by oral corticosteroids
and prescription nonsteroidal anti-inflammatory drugs (NSAIDs) was assessed
by stratification and regression modeling. Individuals with a confirmed event
were classified as exposed to prescription NSAIDs if they were dispensed a
prescription NSAID during the 45 days of eligible person-time before onset
of the event. Persons without an event were classified as exposed if a prescription
NSAID was dispensed during the 45 days preceding a randomly chosen date during
eligible person-time. A similar strategy was used to classify oral corticosteroid
exposure. We used Poisson regression to obtain the hazard rate estimates under
a censored exponential event-time model.21
Confidence intervals were formed with model-robust SEs that are consistent
regardless of the adequacy of the exponential model for the process under
consideration.22
RESULTS
STUDY COHORTS
A total of 6549 eligible men and women 35 years and older had 1 or more
dispensings of alendronate between October 1, 1995, and September 30, 1997.
Analysis was restricted to the 6432 persons who were dispensed the 10-mg tablet
exclusively. Nearly 60% of the alendronate users were 65 years or older, 3%
were younger than 45 years, and 92% were women (Table 1). The median number of 10-mg tablets dispensed per person
during the study period was 180; the median number of dispensings was 3. The
median number of days from October 1, 1995, to the first alendronate dispensing
was 362, ranging from 16 to 730.
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Table 1. Baseline Characteristics of the Study Cohorts
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When comparing the alendronate users with the 33 176 unexposed
subjects, the median chronic disease score for persons exposed to alendronate
was 39% greater than the unexposed group (Table 1). In 25 of 29 drug categories used to compute the chronic
disease score, alendronate users were significantly more likely to have 1
or more dispensings during the year before the first dispensing of alendronate
(or the random start date for the unexposed group). Differences were most
marked for persons being treated for rheumatoid arthritis, asthma, and gastric
acid disorder. Persons dispensed alendronate were 73% more likely to have
been hospitalized at least once for any reason during the prior year than
their unexposed counterparts.
There were 9776 women, 60 years or older, in the fracture group and
3863 women in the corresponding subset of age-sex-HMO–restricted alendronate
users. These 2 groups had similar median chronic disease scores and proportions
of subjects who had at least 1 nonfracture hospitalization during the previous
year (Table 1).
INCIDENCE OF GASTRODUODENAL PERFORATIONS, ULCERS, AND BLEEDING
From the HMO databases, 1376 hospitalizations with 1 or more diagnoses
of interest were identified from the 3 study cohorts. The hospitalizations
were approximately uniformly distributed during the study period. Hospital
records were reviewed for 1041 (76%) of the 1376 potential perforations, ulcers,
or bleeding episodes; study personnel were denied access to most of those
that were not reviewed. The proportion of charts unavailable for review was
similar between alendronate users (28%) and unexposed individuals (30%), but
lower for the fracture cohort (18%).
Alendronate Users vs Unexposed Cohort
Among the alendronate and unexposed cohorts, 167 (28%) cases of upper
gastrointestinal perforation, ulcer, or bleeding were confirmed by record
review; 155 were gastroduodenal and 12 were esophageal. Of the 155 persons
with gastroduodenal perforation, ulcer, or bleeding, 49 (32%) had their event
during at-risk person-time; 14 were alendronate users and 35 were from the
unexposed group. No person had more than 1 confirmed event. For most cases
among the alendronate users, the perforation, ulcer, or bleeding event occurred
at a time relatively distant from their initial alendronate dispensing (median,
198 days). The incidence rates of gastroduodenal perforation, ulcer, or bleeding
at various durations of alendronate therapy were not significantly different
(P = .59; Table
2).
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Table 2. Rate of Confirmed Gastroduodenal Perforation, Ulcers, and
Bleeding by Duration of Alendronate Therapy
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The crude incidence rate of gastroduodenal perforation, ulcer, or bleeding
for the alendronate cohort (3.4 per 1000 person-years) was 3 times (95% CI,
1.6-5.5) greater than the crude rate for the unexposed group (1.1 per 1000
person-years). The IRR was 1.8 (95% CI, 0.8-3.9) after adjustment for age,
sex, chronic disease score, recent exposure to prescription NSAIDs and oral
corticosteroids, and the number of hospitalizations in the year before the
first dispensing of alendronate (or the referent date for the unexposed group; Table 3). When terms for the interaction
of alendronate exposure with prescription NSAIDs and oral corticosteroids
were included in the full model, only the term for corticosteroids significantly
improved the fit of the model (P<.03). Stratified
regression analysis showed an adjusted IRR of 2.8 (95% CI, 1.4-5.8) for those
without recent use of oral corticosteroids and an adjusted IRR of 2.6 (95%
CI, 1.1-6.3) for those with no recent NSAID use. The IRR was less than 1,
with wide CIs, for those with recent use of drugs from either category, but
there were few patients in these strata and the estimates were unstable (data
not shown).
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Table 3. Adjusted Incidence Rate Ratios for Gastroduodenal Perforation,
Ulcers, and Bleeding Derived From Poisson Regression Models*
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The event rate among alendronate users during time not exposed to alendronate
was not significantly different from the rate during alendronate-exposed time
(2.4 vs 3.4 per 1000 person-years; P = .25), but
it was greater than the rate among the unexposed cohort (1.1 per 1000 person-years; P<.001).
Alendronate Users vs Fracture Cohort
Ten of the 14 gastroduodenal perforations, ulcers, or bleeding events
among alendronate users described above were among the 3863 women of the age-sex-HMO–restricted
cohort. There were 58 confirmed gastroduodenal perforations, ulcers, or bleeding
events in the fracture cohort. Crude IRR for age-sex-HMO–restricted
alendronate users relative to the fracture cohort was 1.1 (95% CI, 0.6-2.3).
The IRR was unchanged after controlling for age, chronic disease score, recent
exposure to prescription NSAIDs and oral corticosteroids, and the number of
nonfracture related hospitalizations during the previous year (IRR, 1.1; 95%
CI, 0.6-2.2; Table 3). Interaction
terms between alendronate use and NSAID exposure and alendronate use and oral
corticosteroid exposure were not significant.
When the fracture cohort was further stratified into the hip fracture
group and the nonhip fracture group, the adjusted IRR of gastroduodenal perforations,
ulcers, and bleeding for alendronate users relative to the hip fracture group
(IRR, 0.6; 95% CI, 0.3-1.2) was substantially different from that for alendronate
users relative to the nonhip fracture group (IRR, 1.6; 95% CI, 0.7-3.3). Women
with hip fractures represented only 29% of the fracture cohort, but they generated
more than 50% of the confirmed perforations, ulcers, or bleeding events in
the fracture group.
ESOPHAGEAL PERFORATIONS, ULCERS, AND BLEEDING
There were 20 confirmed esophageal perforations, ulcers, or bleeding
events without gastric or duodenal ulcers; 1 occurred during exposure to alendronate,
5 after the referent date in the unexposed group, 7 among the fracture group,
and the rest occurred during ineligible person-time. No further analysis was
performed for esophageal lesions because of the small number of events.
COMMENT
We conducted a retrospective cohort study of nearly 50 000 persons
to investigate a possible association between alendronate and confirmed gastroduodenal
perforation, ulcer, or bleeding resulting in hospitalization. Because of the
potential for confounding by indication (ie, osteoporosis), estimates of the
effect of alendronate were computed with 2 separate comparison groups. Although
neither estimate was statistically significant, they were substantially different,
with a smaller (nonsignificant) excess risk when the fracture cohort was used
as the comparison group. Not surprisingly, the fracture group was heterogeneous
with respect to the risk of these gastroduodenal events; the adjusted rate
ratios were markedly different when the alendronate group was separately compared
with those with hip fracture and those with nonhip fracture.
We considered osteoporosis a potential confounder of the alendronate
and gastroduodenal perforations, ulcers, and bleeding relationship because
of the increased morbidity and mortality in persons with osteoporosis.12-14 The excess morbidity
can be attributed to underlying diseases and osteoporotic fractures, especially
fractures of the hip and vertebrae23; the consequences
of nonhip fractures such as wrist and humerus are substantially less.12, 24 The relationship between alendronate
use and upper gastrointestinal adverse events is further complicated by the
increased prevalence of gastrointestinal symptoms in the elderly.25 Persons dispensed alendronate in the present study
appeared to have greater morbidity than the unexposed group; they were more
likely to have been hospitalized in the preceding 12 months and their chronic
disease scores were higher. Moreover, they were substantially more likely
to have been dispensed drugs that either predispose to peptic ulcers (eg,
prescription NSAIDs and oral corticosteroids) or are used to treat conditions
that may progress to peptic ulcers (eg, histamine2 antagonists).
Taken together, it appears that persons using alendronate may have had a greater
underlying risk of a gastroduodenal adverse event than persons not using alendronate,
and this may have accounted for the decrease in observed risk after control
for potential confounders. Alendronate recipients' nearly equal rate of perforation,
ulcer, or bleeding during periods when they were not exposed to alendronate
and periods when they were exposed lends further support to this possibility.
The ideal group with which to compare alendronate-exposed persons would
have osteoporosis at the same rate and intensity but without exposure to alendronate.
However, coded diagnoses of osteoporosis were not uniformly available in the
automated databases of the HMOs participating in this study, and the misclassification
inherent in the diagnosis of osteoporosis would result in a biased sample
of persons with osteoporosis. We postulated that a comparison group consisting
of older women (men were excluded from the fracture cohort) with osteoporotic
fractures would be subject to less misclassification, and although not representative
of all persons with osteoporosis, they would be more likely to have osteoporosis
than a randomly selected comparison group. In fact, the general risk profile
of the fracture cohort closely approximated the profile of the corresponding
alendronate cohort; the 2 groups had comparable chronic disease scores and
nonfracture hospitalization rates in the preceding 12 months. It should be
noted, however, that the fracture cohort was not homogeneous with respect
to the risk of gastroduodenal adverse events. Compared with women with nonhip
fractures, those with hip fractures accounted for a disproportionate number
of gastroduodenal perforations, ulcers, and bleeding. We do not know whether
this difference is a reflection of more severe osteoporosis in women with
hip fracture or whether such women have a greater prevalence of other unmeasured
risk factors for these adverse events.
Although gastric and duodenal adverse events were reported in some of
the alendronate clinical trials, their occurrence was no greater in those
treated with alendronate than in the placebo groups.4, 8, 26
Nor were there significant differences between the treatment groups in the
overall incidence of adverse events leading to discontinuation of study medication.
Bauer et al26 combined the 2 study arms of
the Fracture Intervention Trial and determined that the rate of gastroduodenal
adverse events among over 6400 women with osteoporosis was nearly equal in
the alendronate and placebo treatment groups. Although there are important
methodological differences between the Bauer et al study and ours that limit
comparisons (eg, their cases included hospitalized as well as nonhospitalized
cases), the risks of gastroduodenal adverse events appear to be similar. For
example, the event rates among alendronate-exposed women (55-64, 65-74, and
75-84 years old) in the present study were 1.1, 4.9, and 4.4 per 1000 person-years,
respectively. These rates approximate the age-specific rates reported by Bauer
et al.26
Nitrogen-containing bisphosphonates, including alendronate, have the
potential to cause mucosal irritation. Studies in laboratory animals have
demonstrated that alendronate is a topical irritant capable of inflicting
erosions and enhancing indomethacin-induced ulceration of the esophagus and
stomach.27-28 In addition, a number
of case reports have described esophagitis and esophageal ulcers subsequent
to ingestion of alendronate.9-10,29-31
Less common and conflicting have been reports of alendronate-associated gastroduodenal
ulcers.11, 32 A retrospective cohort
study determined that older women taking alendronate were more likely to experience
acid-related disorders of the upper gastrointestinal tract than a group of
nonalendronate users not selected for osteoporosis.33
Our study had approximately 65% power to detect a 2-fold increase in
risk of gastroduodenal perforations, ulcers, and bleeding for the comparison
between the alendronate and the unexposed cohorts. Additional limitations
pertain to the type and level of detail in automated medical records. We had
no data on risk factors such as alcohol use, smoking, Helicobacter
pylori infection, or family history of osteoporosis and peptic ulcer
disease. Perhaps more important, we had no information on over-the-counter
medications, such as nonprescription NSAIDs, that are known to promote gastrointestinal
ulcers.16 If the alendronate-exposed individuals
in our study, who were significantly more likely to have filled prescriptions
for NSAIDs, were also more likely to use over-the-counter NSAIDs than those
not exposed to alendronate, then we may have overestimated the relative risk
of gastroduodenal perforations, ulcers, and bleeding. We probably overestimated
exposure since we assumed that all dispensed alendronate tablets were taken,
and we have no method to evaluate compliance using automated data. This type
of misclassification of exposure would bias the effect measure toward an apparent
null effect. Although the fracture types that defined the fracture cohort
were known to be associated with osteoporosis,1, 34
it is likely that some individuals in the fracture cohort did not have osteoporosis.
Although we were not able to review all potential cases of outcomes of interest,
the very specific confirmation criteria that we used for gastroduodenal perforations,
ulcers, and bleeding make it unlikely that this would have biased the estimate
of the relative risk.35
The choice of an appropriate comparison group is crucial to the understanding
of the association between alendronate and gastroduodenal perforations, ulcers,
and bleeding. To the extent that osteoporosis is a risk factor for these adverse
events, the observed relative risk derived by comparing alendronate users
with a group with less morbidity and lower prevalence of osteoporosis (randomly
selected, not exposed to alendronate) is probably an overestimate. To the
extent that nonpathologic fractures are good markers for osteoporosis in older
women, the measure of effect derived by comparing alendronate users with those
with selected fractures may be more accurate. It is also possible that the
fracture cohort, nearly 30% of which had a hip fracture, had a greater level
of morbidity, and the rate ratio would be biased toward the null. These results
underscore the need to consider the severity of osteoporosis and comorbidity
to properly interpret the risk of gastroduodenal adverse events in patients
being treated for osteoporosis.
Although the crude analysis demonstrated a 3-fold increase in the risk
of gastroduodenal perforations, ulcers, and bleeding among patients dispensed
alendronate, a substantial fraction of this association was attributable to
comorbid conditions and other factors. The role of osteoporosis as inferred
from fractures is both important and complex; countervailing risks of gastroduodenal
adverse events depended on the presence of hip fractures in the comparison
group. A clearer understanding of the morbidity associated with osteoporosis
would more completely elucidate the relationship between alendronate use and
gastroduodenal perforations, ulcers, and bleeding.
AUTHOR INFORMATION
Accepted for publication August 27, 2001.
This study was supported by a research grant from Merck & Co, Inc.
We greatly appreciate the contributions of Emily Cain, Rachel Dokholyan,
and Parker Pettus. We are also grateful to Mike Allison, Charlotte Corelle,
Therese DeFor, Jennifer Ellis, Barbara Mendius, Jill Mesa, Alice Pressman,
Marsha Raebel, and Deborah Wood.
This study was presented, in part, as a poster at the 16th International
Conference on Pharmacoepidemiology, Barcelona, Spain, August 20-23, 2000.
Corresponding author and reprints: K. Arnold Chan, MD, ScD, Channing
Laboratory, Brigham and Women's Hospital, 181 Longwood Ave, Boston, MA 02115
(e-mail: kachan{at}hsph.harvard.edu).
From the Channing Laboratory, Department of Medicine, Brigham and Women's
Hospital, and Harvard Medical School, Boston, Mass (Drs Donahue, Chan, Carey,
and Platt); Department of Epidemiology, Harvard School of Public Health, Boston,
Mass (Dr Chan); Meyers Primary Care Institute, Fallon Healthcare System, and
University of Massachusetts Medical School, Worcester (Drs Andrade and Gurwitz);
Kaiser Permanente Colorado, Denver (Dr Beck); Kaiser Permanente Northwest,
Portland, Ore (Dr Boles); Group Health Cooperative, Seattle, Wash (Drs Buist,
Fishman, and La Croix); Merck & Co, Inc, West Point, Pa (Drs Chandler
and Guess); Henry Ford Health System, Detroit, Mich (Dr Chase); Kaiser Permanente
Medical Care Program, Oakland, Calif (Drs Ettinger and Levin); HealthPartners
Research Foundation, Minneapolis, Minn (Dr Goodman); University of California,
San Francisco, School of Medicine (Dr Levin); and Department of Ambulatory
Care and Prevention, Harvard Medical School, and Harvard Pilgrim Health Care,
Boston, Mass (Dr Platt). Dr Ettinger received grant support from Eli Lilly,
Merck & Co, Solvay, Berlex, Proctor and Gamble, and Novogen and was a
paid consultant for Eli Lilly, Solvay, Berlex, Proctor and Gamble, and Durbied.
Dr Levin received research support from Novartis and Merck & Co. Drs Chandler
and Guess are employees and stockholders in Merck & Co.
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