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Our purpose was to characterize the occurrence of gastrointestinal (GI) events among women on oral bisphosphonate therapy.
Methods
This was a retrospective cohort study that used a United States (US) claims database. The study period was from January 1, 2000, to December 31, 2011. The index date was the date of the first oral bisphosphonate (alendronate, ibandronate, or risedronate) prescription and occurred between January 1, 2001, and December 31, 2010. The pre- and post-index periods were the 1-year periods before and after the index date, respectively. The analysis included women with osteoporosis aged ≥55 years at the index date who were naive to all osteoporosis treatments before the index date and were continuously enrolled in the health plan for at least 1 year before and 1 year after the index date. Patients with a diagnosis of malignant neoplasm during the pre- or post-index periods or a diagnosis of Paget disease anytime in the claims history were excluded. The occurrence of GI events (defined as esophagitis; gastroesophageal reflux disease; ulcer, stricture, perforation, or hemorrhage of the esophagus; gastric, duodenal, or peptic ulcer; acute gastritis; duodenitis; GI hemorrhage; nausea/vomiting; or dysphagia) was assessed during the pre-index period and at 3, 6, and 12 months in the post-index period. The rate of GI events was defined as the percentage of patients having at least 1 GI event in each analysis period (ie, pre-index and post-index periods). GI events in the post-index period were also stratified by the presence of GI events in the pre-index period.
Findings
A total of 75,593 women were included in the analysis. The average age at the index date was 64.4 years. Gastroprotective agents were used by 17.9% of patients. Approximately one fourth of patients (26.6%; n = 20,073) had ≥1 GI events in the pre-index period. Approximately the same proportion of patients (28.0%; n = 21,142) experienced GI events in the post-index period. The cumulative rate of GI events during the post-index period was higher among patients who had GI events in the pre-index period (51.2%) than among patients without a GI event in the pre-index period (19.6%).
Implications
Among women with osteoporosis enrolled in a US commercial plan, GI events were common regardless of bisphosphonate use. Approximately one fourth of US women on bisphosphonate therapy experienced GI events within the year after initiation of therapy, and one half of US women with a previous GI event had another event while taking bisphosphonates.
Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause 2010;17:25-54; quiz 55-56.
American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis.
Many therapies are available with proven efficacy for reducing fracture risk in patients with osteoporosis. Among them, the oral bisphosphonates, including alendronate, risedronate, and ibandronate, are the most commonly used agents.
Oral bisphosphonates can cause irritation of the gastrointestinal (GI) tract
Studies of the frequency of GI events among patients who used oral bisphosphonates in real-world clinical practice have found that the experience of a GI event increases the likelihood of discontinuation,
and discontinuation precludes the reduction of fracture risk.
However, the understanding of the occurrence of GI events and characterization of GI events among patients who used oral bisphosphonates, particularly in the US-managed care population, is limited. It is important for treating physicians to know how many bisphosphonate users, and which ones, will experience GI events so that they can be ready with educational support and regimen adjustments to help these patients maintain their reduction in osteoporosis fracture risk. The objective of this study was therefore to determine the proportion and characteristics of US bisphosphonate users who experience GI events.
Methods
Data Source
The retrospective cohort study was conducted with the i3 InVision Data Mart (i3, Ann Arbor, Michigan; now the Clinformatics Data Mart; Optum, Eden Prairie, Minnesota). This large, nationwide US claims database contains de-identified patient information, including demographic characteristics and medical and pharmacy claims data. Medical claims include International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis and procedure codes. The outpatient pharmacy claims data contain National Drug Codes for dispensed medications. More than 3 million patients with a diagnosis of osteoporosis, osteoporosis-related fracture, and/or a prescription for a medication used to treat or prevent osteoporosis were included in the database during the study period from January 2000 through December 2011.
Study Design
The index date, which could occur any time between January 1, 2001, and December 31, 2010, was defined as the date of the first oral bisphosphonate prescription. The pre-index period was the 12 months before the index date, and the post-index period was the 12 months after the index date. The analyses used de-identified patient data; thus, informed consent was not required.
Study Sample
Eligible patients were women aged ≥55 years with a diagnosis of osteoporosis (ICD-9 code 733.0), 1 new pharmacy claim for an oral bisphosphonate (alendronate, risedronate, or ibandronate) on the index date, and continuous enrollment in the health plan during the pre- and post-index periods. Patients were excluded if they had a pharmacy claim for any osteoporosis therapy at any time during the pre-index claims history, a medical claim for Paget disease (ICD-9 code 731.0x) at any time during the claims history, or a diagnosis of malignant neoplasm (ICD-9 codes 140.xx–171.xx, 174.xx–208.xx, or 230.xx–239.xx) during the pre- or post-index periods.
Study Variables
Patient age was assessed on the index date. Characteristics assessed within 1 year before the index date were the Deyo-Charlson comorbidity index score
and the use of gastroprotective agents, glucocorticoids, estrogen, and NSAIDs. Disease diagnoses and comorbidities were identified on the basis of ICD-9 codes, and medications were identified on the basis of National Drug Code numbers. Similar to previous publications,
GI events were identified on the basis of ICD-9 diagnosis codes for esophagitis; gastroesophageal reflux disease; ulcer, stricture, perforation, or hemorrhage of the esophagus; gastric, duodenal, or peptic ulcers; acute gastritis; duodenitis; GI hemorrhage; nausea/vomiting; or dysphagia. The following codes were defined as severe GI events: 530.21 (ulcer of the esophagus with bleeding), 530.4 (perforation of esophagus), 530.82 (esophageal hemorrhage), 531.x (acute or chronic gastric ulcer with hemorrhage and/or perforation), 532.x (acute or chronic duodenal ulcer with hemorrhage and/or perforation), 533.x (acute or chronic peptic ulcer with hemorrhage and/or perforation), 535.0x (acute gastritis), and 578.xx (GI hemorrhage).
Statistical Analysis
Patient characteristics and GI event rates were analyzed descriptively. Pre-index patient characteristics were assessed in all patients and compared for patients with versus without post-index GI events. Means and SDs were used for continuous variables, and numbers and percentages were used for categorical variables. Between-cohort differences were assessed with t tests for continuous variables and χ2 tests for categorical variables. The between-cohort difference was considered statistically significant if the P value was ≤0.05.
The primary outcome of interest was the rate of GI events, which is presented for the pre-index period as the percentage of patients who experienced an event during the 12 months before the index date and, for the post-index period, as the cumulative percentage of patients who experienced GI events at 3, 6, and 12 months after the index date. In addition, the cumulative 3-, 6- and 12-month GI event rates were calculated and reported after stratification by the presence of pre-index GI events
Results
Characteristics of the Study Population
After application of the inclusion and exclusion criteria, 75,593 women were eligible for the analysis (Figure 1). The average age at the index date was 64 years, and 17.9% of patients used gastroprotective agents during the pre-index period (Table). One quarter of the women (25.1%) used NSAIDs (Table). Use of gastroprotective agents in the pre-index period was significantly higher in patients who experienced post-index GI events (34.3% vs 11.5% in patients without post-index GI events; P < 0.001; Table). Likewise, a history of NSAID use, glucocorticoid use, and estrogen use was more common in patients with post-index GI events (30.9%, 22.1%, and 22.2%, respectively) than in patients without post-index GI events (22.9%, 15.5%, and 21.0%, respectively; all, P < 0.001; Table). Patients with post-index GI events had a higher comorbidity score than patients without GI events (0.8 vs 0.5; P < 0.001; Table). GI events ranged from mild symptoms such as heartburn to serious events such as perforation of the esophagus, stomach, or duodenum.
A total of 20,073 women (26.6%) had at least 1 GI event in the pre-index period, and 21,142 women (28.0%) had at least 1 GI event in the post-index period. Severe GI events occurred in 2707 women in the pre-index period (3.6%) and in 2966 women in the post-index period (3.9%). Pre-index GI events had occurred in 48.6% of patients with a GI event in the post-index period, compared with 18.0% of patients without a post-index GI event (P < 0.001; Table). The proportion of patients with severe pre-index GI events was higher among patients with post-index GI events than among patients without post-index GI events (6.5% vs 2.4%; P < 0.001; Table).
Figure 2 shows the rate of GI events at predetermined time points within the post-index period. In the total study population, 10.7%, 17.5%, and 28.0% experienced GI events within the first 3, 6, and 12 months, respectively, of bisphosphonate initiation. Totals of 903 (1.2%), 1653 (2.2%), and 2966 (3.9%) women experienced severe GI events at these respective time points. The frequencies were higher in women who had experienced GI events in the pre-index period (23.0%, 35.3%, and 51.2%, respectively) than in women with no GI events in the pre-index period (6.3%, 11.1%, and 19.6%, respectively).
Figure 2Percentage of patients who experienced a GI event during the post-index period. GI = gastrointestinal.
This study found that, in US women who initiated bisphosphonate therapy, the overall rate of GI events after initiating bisphosphonates is approximately the same as before initiation. Post-initiation GI events occurred more frequently in patients with a history of GI events.
GI symptoms are common in populations with osteoporosis, making it difficult to distinguish background GI symptoms from those caused by medication use. In a survey of 497 women from the New York City area, 47% of postmenopausal women reported having upper GI symptoms (compared with 42% of perimenopausal women and 26% of premenopausal women).
reported that Danish patients who started various osteoporosis therapies were already at increased risk of GI events, such as esophagitis, esophageal ulceration/perforation, and gastroduodenal ulcers, before taking the medications. Similarly, several US observational studies that reported both pre-initiation and post-initiation GI event rates found that the rate in the pre-initiation period was similar to (or greater than) that in the period of bisphosphonate use.
The rate of GI events among women treated with osteoporosis therapy in our study population (28.0%) was higher than that reported in previous US studies of bisphosphonate users.
Differences in sex distribution (ie, percentage of men), the definition of GI events, and the specific bisphosphonate(s) being assessed likely contributed to the differences in the results. Studies of postmenopausal women treated with bisphosphonates in various European countries, however, have reported GI event frequencies in the range of 9.9% to 51.6%,
Compliance and satisfaction with raloxifene versus alendronate for the treatment of postmenopausal osteoporosis in clinical practice: an open-label, prospective, nonrandomized, observational study.
Differences in persistence, safety and efficacy of generic and original branded once weekly bisphosphonates in patients with postmenopausal osteoporosis: 1-year results of a retrospective patient chart review analysis.
Our observation that GI events among women treated with osteoporosis therapy are more common in patients with a history of GI events confirms the findings of several previous studies. Among UK women taking risedronate, the rates of upper GI adverse effects in women with and without pretreatment GI problems were 32% and 11%, respectively (P < 0.002).
In another UK population that switched from risedronate to alendronate, a history of upper GI events was associated with a >3-fold increased risk of emergent upper GI events (hazard ratio = 3.18; 95% CI, 2.79–3.63).
A Grecian cohort who took alendronate exhibited more than twice the odds of GI-related adverse events if they had a history of GI disease (odds ratio = 2.4; 95% CI, 1.4–3.8).
Similarly, our finding that patients with post-index GI events were more frequent users of NSAIDs and glucocorticoids is consistent with previous analyses finding that use of these drugs was predictive of GI events.
Limitations of our study design include the typical weaknesses of claims database analyses, such as potential coding errors/omissions and the assumption of compliance on the basis of prescription refills. In addition, our combined analysis of different bisphosphonates does not take into account their individual tolerability profiles. We report here an average effect of the drug class as a whole. Our study population did not include a control group, so we cannot quantitatively distinguish between the competing factors that may be responsible for the relatively stable GI event rates before and after bisphosphonate initiation. Likewise, we cannot say whether the GI event rates in an untreated control group would have remained stable. Finally, the definition of GI events differs across studies, and, as suggested in the third paragraph of this Discussion, the event rate will vary according to the severity of GI events.
Conclusions
This study found that GI events are common among women with osteoporosis both before and during bisphosphonate use. Among US women enrolled in a commercial health plan and taking bisphosphonate therapy, one fourth experienced a GI event within a year. Approximately one half of US women with a previous GI event had another event while taking bisphosphonates. Prescribing physicians should target their patients with a history of GI events for follow-up about their treatment experience, and future studies should evaluate the burden of GI events as it relates to resource use in the osteoporotic patient population.
Conflicts of Interest
A. Modi and S. SSajjan are employees of Merck & Co., Inc. C.-P. Steve Fan is an employee of Asclepius Analytics LLC, which has received financial remuneration from Merck & Co., Inc. to participate in the study. E. Siris received financial remuneration from Merck & Co., Inc. for the design of the study and the clinical analysis of the results. This study was funded by Merck & Co., Inc. Other than through the employer relationship disclosed here, Merck & Co., Inc. did not have a role in the study design, data collection, interpretation of the data, in writing of the manuscript, and in the decision to submit the manuscript for publication.
Acknowledgments
We thank Anna Kaufman, MPH, and Melissa Stauffer, PhD, in collaboration with SCRIBCO, for medical writing assistance.
All authors participated in study design, data interpretation, and critical revisions of the manuscript. C.-P. Steve Fan was responsible for data collection and analysis. All authors approved the final version of the manuscript.
References
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The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine.
Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause 2010;17:25-54; quiz 55-56.
American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis.
Compliance and satisfaction with raloxifene versus alendronate for the treatment of postmenopausal osteoporosis in clinical practice: an open-label, prospective, nonrandomized, observational study.
Differences in persistence, safety and efficacy of generic and original branded once weekly bisphosphonates in patients with postmenopausal osteoporosis: 1-year results of a retrospective patient chart review analysis.
P < 0.001 for the comparison between patients with and without post-index GI events.
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