Bisphosphonate Use May Promote Higher Risks for Uveitis, Scleritis CME

News Author: Jennifer Garcia CME Author: Dsire Lie, MD, MSEd Faculty and Disclosures CME Released: 04/09/2012; Valid for credit through 04/09/2013

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CLINICAL CONTEXT
According to the current study by Etminan and colleagues, bisphosphonates are the most frequently prescribed medications for the prevention of osteoporosis, and literature on safety has focused on long-term effects such as atypical fractures, atrial fibrillation, and esophageal cancer. Case reports of uveitis and scleritis have been documented with the use of alendronate and risedronate, and in most cases, symptoms occurred within days of starting bisphosphonates. This retrospective linked database cohort study examines the association between first-time use of bisphosphonates and the risks for uveitis and scleritis.

STUDY SYNOPSIS AND PERSPECTIVE

Patients taking oral bisphosphonates for the first time may be at higher risk of developing scleritis and uveitis, according to a large, retrospective cohort study published online April 2 in the Canadian Medical Association Journal. The incidence rate among 10,827 first-time bisphosphonate users was 29/10,000 person-years for uveitis and 63/10,000 personyears for scleritis. In contrast, the incidence rate among 923,320 nonusers was 20/10,000 person-years for uveitis and 36/10,000 for scleritis. This resulted in an elevated risk for uveitis among firsttime users (adjusted relative risk [RR], 1.45; 95% confidence interval [CI], 1.25 - 1.68) and scleritis (adjusted RR, 1.51; 95% CI, 1.34 - 1.68). The researchers also found that bisphosphonate users were older and more likely to be women compared with nonusers. "This is the first study that quantifies the risk of uveitis and scleritis with these drugs. In the past, much attention has been given to

other adverse events related to these drugs, mainly linking them [to] increasing the risk of atypical fractures, atrial fibrillation, and gastrointestinal cancer," lead author Mahyar Etminan, PharmD, MSc, from the Pharmaceutical Outcomes Programme, Child and Family Research Institute, and the Department of Medicine, University of British Columbia, Vancouver, Canada, said in an interview with Medscape Medical News. "These findings are important because [they] bring to light another important adverse event, mainly ocular, that clinicians and patients may not have known about," he continued. Dr. Etminan and colleagues analyzed data from the British Columbia Linked Health Database. They included all patients who had visited an ophthalmologist between January 2000 and December 2007 and who had at least 1 year of information about prescription drug use. Only those patients using bisphosphonates for the first time were included. The researchers followed-up all patients until one of the following occurred: the development of uveitis or scleritis, death, termination of health coverage, or the end of the study period. Patients who had received more than 1 prescription for bisphosphonates were excluded. In the statistical analysis, adjustments were made for the following covariates: age, sex, calendar time, and history of ankylosing spondylitis, diabetes, inflammatory bowel syndrome, systemic lupus erythematosus, multiple sclerosis, psoriasis, rheumatoid arthritis, and sarcoidosis. Adjustments were also made for the use of sulfa-containing medications, as these have been shown to increase the risk for inflammatory eye disease. The researchers note that previously reported cases of ocular adverse events with the use of oral bisphosphonates were primarily associated with alendronate and risedronate. "The unanswered question is whether the risk of uveitis and scleritis is different with each individual bisphosphonate," Dr. Etminan said. According to the researchers, it is possible that the release of inflammatory mediators triggered by the use of bisphosphonates may be the mechanism behind the development of scleritis and uveitis among first-time users. The authors acknowledge that, because of the retrospective nature of the study, there were limitations such as the inability to verify

that cases were not misclassified. In addition, they could assess drug dispensing, but not drug intake. "The results of our study are consistent with an increase in the risk of scleritis and uveitis with the use of oral bisphosphonates," Dr. Etminan and colleagues write. Left untreated, uveitis can lead to cataracts, glaucoma, macular edema, and scleral perforation. "Our study highlights the need for clinicians to inform their patients about the signs and symptoms of scleritis and uveitis, so that prompt treatment may be sought and further complications averted," the authors conclude. "This study strongly confirms the suggestion of a smaller, earlier epidemiologic survey," said Roger Steinert, MD, director of the Gavin Herbert Eye Institute at the University of California, Irvine, who was not involved in the study. "Oral bisphosphonates do increase the risk of uveitis and scleritis in first-time users by approximately 50%." "Fortunately, the incidence of uveitis and scleritis is still low, and not a contraindication to oral bisphosphonates in persons at risk for osteoporosis," Dr. Steinert told Medscape Medical News. "However, ophthalmologists need to be alert to this potential cause of ocular inflammation and obtain a history specifically inquiring about first-time use of these drugs when evaluating new-onset uveitis and scleritis." Funding for the study was provided by the Canadian National Institute for the Blind. The authors and Dr. Steinert have disclosed no relevant financial relationships. CMAJ. Published online April 2, 2012.

STUDY HIGHLIGHTS
The study used the British Columbia Linked Health Database with data files that include a comprehensive prescription drug database (PharmaNet), and Medical Health Services data files documenting clinician healthcare visits. The cohort comprised all persons who visited an ophthalmologist between 2000 and 2007. The date of the first visit was designated as the date of cohort entry.

 Exposure was defined as the first and only prescription for an oral bisphosphonate after entry. Only first-time users of bisphosphonates were included, and those who received multiple prescriptions were excluded. Nonusers were defined as those who had not received a prescription for bisphosphonates during the follow-up period. Cohort members were observed until uveitis or scleritis developed, or death, termination of health coverage, or the end of the study period, whichever came first. Case patients were people who had a first diagnosis of uveitis or scleritis by use of International Classification of Diseases, Ninth Revision, codes for identification. From 2000 to 2007, a total of 989,591 people visited an ophthalmologist. After exclusion of those with more than 1 prescription for a bisphosphonate, the cohort comprised 10,827 first-time bisphosphonate users and 923,320 nonusers. Bisphosphonate users were older, more likely to be women, and more likely to have longer follow-up than nonusers. Age at cohort entry was 68.7 years for users and 51.3 years for nonusers, and 22.3% of users were men compared with 48.4% of nonusers. The incident rate among users was 29 per 10,000 person-years for uveitis and 63 per 10,000 person-years for scleritis. For nonusers, the respective incident rates were 20 per 10,000 person-years and 36 per 10,000 person-years. The relative risk in users of bisphosphonates was 1.45 for uveitis, and the number needed to harm was 1100. The relative risk for scleritis among first-time bisphosphonate users was 1.51, and the number needed to harm was 370. The authors concluded that risks for both uveitis and scleritis prevail among first-time users of bisphosphonates and that clinicians should educate patients about signs and symptoms of these conditions when prescribing the medication.

CLINICAL IMPLICATIONS
First-time use of an oral bisphosphonate is associated with an increased risk for uveitis.

First-time use of an oral bisphosphonate is associated with an increased risk for scleritis.