Are Oral Bisphosphonates Associated With Risk for Wet AMD?

Post on September 22, 2016 by André Broussard, D.C.

William C. Ou; Charles C. Wykoff, MD, PhD
September 23, 2016

Bisphosphonates: A Staple of Osteoporosis Treatment

Osteoporosis is a disease characterized by weak and brittle bones that affects 10 million Americans over the age of 50 years and leads to 1.5 million bone fractures annually in the United States.[1,2] Several mechanisms can underlie this condition, including inadequate development of bones during growth, excessive rates of bone resorption, and insufficient formation of new bone.[3]

Postmenopausal women are particularly susceptible to osteoporosis, with 9%-38% of women older than 50 years in developed countries affected vs 1%-8% of men in the same age group.[4] This difference is largely due to declining estrogen levels after menopause, which is linked to an increase in net bone resorption.[3,5] Other risk factors include age, body mass index, smoking, and glucocorticoid use.[6]

Because osteoporosis cannot be cured, considerable emphasis is placed on prevention. Adequate daily intake of calcium (1200 mg) and vitamin D (800-1000 IU), regular exercise, and maintenance of a healthy diet and body weight can all contribute to keeping bones healthy.[6]

Bisphosphonates are the class of pharmaceuticals most widely used to prevent and treat osteoporosis, with an estimated 15 million oral bisphosphonate prescriptions dispensed annually in the United States.[7] These drugs induce apoptosis in bone-resorbing osteoclasts, thereby slowing down the rate of bone loss.[8] Some of the most commonly prescribed oral bisphosphonates are alendronate, risedronate, and ibandronate. Gastrointestinal complications, such as nausea, dyspepsia, and abdominal pain, are the most commonly reported side effects. In rare cases, patients can develop osteonecrosis of the jaw.[8,9]

Age-Related Macular Degeneration: Background

Age-related macular degeneration (AMD) is the leading cause of vision loss in many developed countries, with approximately 2 million people in the United States affected.[10,11] The advanced neovascular or “wet” form of AMD can be particularly debilitating and is characterized by abnormal growth of blood vessels under and into the light-sensing part of the retina in a process called “choroidal neovascularization.”[10,12] These blood vessels can leak fluid and bleed, leading to loss of central vision. Smoking habits[13] and the use of specific supplements, as determined by the Age-Related Eye Disease Study (AREDS)[14] and AREDS2[15] trials, are the most significant modifiable risk factors for AMD.

Bisphosphonate Use and AMD: Are They Related?

Given the prevalence of both oral bisphosphonate use and wet AMD, there has been interest in elucidating the relationship between them, if one exists. Recently, Mammo and colleagues[16] reported the results of a retrospective analysis of bisphosphonate use and AMD incidence using three distinct approaches.

The first approach was a disproportionality analysis comparing the number of AMD cases reported alongside bisphosphonates vs all other drugs. The second was a case/control study comparing wet AMD cases with controls who had documented visits to an ophthalmologist but no AMD diagnosis. The third was a self-controlled case series comparing AMD risk within individual cases before and after bisphosphonate exposure. The disproportionality analysis was based on the US Food and Drug Administration Adverse Event Reporting System database. The latter two analyses were based on the British Columbia Ministry of Health Databases.

The disproportionality analysis revealed relative odds ratios of 3.82 (58 cases), 2.40 (17 cases), and 2.87 (11 cases) for alendronate, ibandronate, and risedronate, respectively. The odds ratios reported from the case/control study (6367 cases and 63,670 controls) were 1.24 for patients with 1 year of bisphosphonate exposure and 1.59 for patients with 3 years of bisphosphonate exposure. In the self-controlled case series (193 cases), the rate ratio for 1 year of bisphosphonate exposure was 1.22 and increased with duration of exposure to 1.87 at 5 years. In sum, the authors concluded that oral bisphosphonate use is associated with a heightened risk of developing wet AMD, with relative risk increasing with increasing duration of bisphosphonate use.

The key strengths of this study are the exceptionally large databases used and the well-controlled analyses. However, the study is not without shortcomings. Most important, the study was observational, meaning that one must consider the old adage that “correlation does not imply causation.” By necessity of their design, observational studies fall lower on the hierarchy of evidence than randomized controlled trials. Even with well-designed controls, the possibility of confounding variables exists. For example, the authors noted that data for cases and controls were collected from two different periods, introducing the possibility that changes in prescribing trends may have influenced the results.[16]

Despite the limitations, the results of this study remain interesting and warrant further inquiry. If validated, the link between bisphosphonates and AMD may be explained through localized inflammatory pathways. Several studies have identified inflammation as a possible risk factor for AMD.[17,18] In turn, bisphosphonates are believed to be proinflammatory. Specifically, they initiate an inflammatory cascade by activating T lymphocytes and upregulating systemic markers of inflammation, such as C-reactive protein, interleukin-6, and interleukin-8.[19,20]

Ocular consequences of this inflammatory trigger have been documented, including cases of orbital inflammation, scleritis, and uveitis.[9,21-23] In many cases, ocular symptoms presented within days of starting bisphosphonate therapy and discontinued upon withdrawal of the drug. However, these events are rare, and it remains unclear whether the relationship is causal.

Although bisphosphonates have effects that could explain an acceleration of AMD, they have also demonstrated antiangiogenic properties that may counteract neovascularization associated with wet AMD.[20,24] One study even reported a therapeutic effect of bisphosphonates in patients with choroidal neovascularization secondary to wet AMD or pathologic myopia.[25] Certainly, additional work is needed to resolve these seemingly paradoxical reports.

Conclusion

Mammo and colleagues[16] reported that the use of oral bisphosphonates is associated with an increased risk for wet AMD. Although the study was well-conducted, limitations inherent in its observational nature and the relative scarcity of other published data mean that it is still too early to draw definitive conclusions about the relationship between bisphosphonates and AMD. Nonetheless, this study highlights the relevance of this issue and serves as an impetus for further epidemiologic and prospective studies.

References

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