Eyeing Another Risk from Bisphosphonates
Abstract & Commentary
By Rahul Gupta, MD, MPH, FACP
Clinical Assistant Professor, West Virginia University School of Medicine, Charleston, WV
Dr. Gupta reports no financial relationships relevant to this field of study.
Synopsis: People using oral bisphosphonates for the first time may be at a higher risk of developing ocular inflammatory adverse events such as scleritis and uveitis.
Source: Etminan M, et al. Inflammatory ocular adverse events with the use of oral bisphosphonates: A retrospective cohort study. CMAJ 2012;184:E431-E434.
BISPHOSPHONATES ARE WIDELY USED FOR THE PREVENTION and treatment of osteoporosis as well as bone loss and skeletal-related complications resulting from malignancy associated with bone metastases. This class of medications was found to be well tolerated and safe during large-scale clinical trials, which led to their approval and their popularity. However, a number of potential adverse effects have been identified and associated with their long-term use. These have included gastrointestinal intolerance, osteonecrosis of the jaw, atypical fractures, oesophageal cancer, atrial fibrillation, and chronic musculoskeletal pain.1
Current evidence also suggests that there may be an association between bisphosphonate therapy and ocular adverse effects, but the extent of this risk remains unclear. Bisphosphonates have been reported to cause a variety of ocular side effects, most of which are inflammatory in nature. Uveitis and scleritis are two such ocular inflammatory diseases that are associated with major morbidity and have been linked to oral bisphosphonate use.2
In their research, Etminan et al conducted a retrospective cohort study using a comprehensive database consisting of residents of British Columbia. The cohort consisted of all of the 934,147 patients who visited an ophthalmologist from January 2000 to December 2007. There were 10,827 first-time users of bisphosphonates and 923,320 nonusers. All the patients who were first-time users of oral bisphosphonates were followed to the first inflammatory ocular adverse event (either scleritis or uveitis), death, termination of insurance, or the end of the study period. The researchers found that the incidence rate among first-time users was 29/10,000 person-years for uveitis and 63/10,000 person-years for scleritis. In contrast, the incidence among people who did not use oral bisphosphonates was much lower at 20/10,000 person-years for uveitis and 36/10,000 for scleritis. The corresponding numbers needed to harm were 1,100 and 370, respectively. First-time users of bisphosphonates were about 50% more likely than nonusers to develop uveitis and scleritis. First-time users also had significantly elevated risks of both uveitis and scleritis after adjustment for other risk factors (rate ratios, 1.45 and 1.51). These associations persisted in an analysis that took into account propensity scores (rate ratios, 1.50 and 1.53). Additionally, the association for scleritis persisted in a sensitivity analysis in which nonsteroidal anti-inflammatory drug use was added to the definition for scleritis (rate ratio, 1.38). The authors also noted that uveitis and scleritis may be more under-reported than other adverse events that are associated with the chronic use of bisphosphonates, such as atypical fracture and cancer.
Commentary
Most of the post-marketing adverse events are initially presented as case reports or observational studies with variable levels of supporting evidence for plausibility and causality. Yet when these reports become public, both patients and physicians may be alarmed out of proportion to the actual effect on a therapeutic regimen. Similarly, several case reports and case series have described a possible relationship between the use of oral bisphosphonates and anterior uveitis and scleritis.3 In most circumstances, symptoms occurred within days of starting the oral bisphosphonate therapy and resolved upon stopping the drug. Since case reports and observational studies may not provide the best estimates of the relative risk of adverse events in the exposed population vs placebo, the findings of Etminan et al are significant. Their study found that patients using oral bisphosphonates for the first time may be at higher risk of scleritis and uveitis compared to people with no bisphosphonate use. Release of inflammatory mediators may be a possible mechanism for bisphosphonate-induced inflammatory events, including ocular disease.
In cases of bisphosphonate-induced uveitis and scleritis, early recognition and intervention can potentially reverse these conditions and prevent significant visual morbidity. Since the majority of oral bisphosphonates are prescribed by the primary care physician, it may be worthwhile to note that the risk of inflammatory ocular adverse events, including scleritis and uveitis, is not highlighted in most package inserts included with oral bisphosphonates but only mentioned under post-marketing experience. It is therefore vital that physicians understand this significant and reversible adverse effect and discuss it with patients being initiated on bisphosphonates so that when it does occur, prompt treatment can be sought and a catastrophe averted.
References
1. Lewiecki EM. Drugs 2011;71:791-814.
2. McKague M, et al. Can Fam Physician 2010;56:1015-1017.
3. Fraunfelder FW, et al. Am J Ophthalmol 2003;135:219-222.
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