This study of a U.S. national population–based sample of adults 40 years of age and older found that participants who consumed ≥800 mg/d of supplementary calcium or ≥18 mg/d of supplementary iron had significantly higher odds of self-reported glaucoma than those who reported no supplemental intake, after adjustment for potential confounders. These nutrient intake levels were equivalent to the highest quintile of calcium intake and the highest two quintiles of iron intake in this population. Concurrent consumption of both calcium and iron at these levels was associated with even greater odds of glaucoma. We did not, however, find a clear dose–response relationship between quintiles of supplementary calcium or iron intake and self-reported glaucoma. Rather, the relationship appeared to suggest a threshold level of oxidant consumption above which there is substantially increased risk of glaucoma. While the concurrent consumption of calcium and iron below threshold levels did not increase the odds of glaucoma, suggesting that there is no significant additive effect of oxidant supplementation below 800 mg/d of calcium and 18 mg/d of iron, the consumption of both oxidants above these threshold levels resulted in even greater odds of glaucoma. It is noteworthy that the threshold levels deemed to be associated with glaucoma risk in this population-based study are considerably lower than the tolerable upper intake levels of calcium (2000 mg/d for those aged ≥51 years)12
and iron (45 mg/d for those aged ≥19 years)13
established by the Institute of Medicine for total nutrient intake.
It can be hypothesized that the detrimental health effects of supplementary iron intake may be because it is a potent oxidant that accumulates in the body with age. Consumption of supplementary iron has recently been associated with increased total mortality among elderly women.14
Furthermore, prior in vitro studies have suggested potential biologic mechanisms by which intracellular iron may be related to glaucoma, with Lin et al.,5
observing that redox-active iron was elevated in TM cells that were chronically stressed in a hyperoxic model. Changes in expression of iron homeostasis genes were also observed, whereas intracellular chelation of iron protected against apoptosis caused by H2
Farkas et al.4
observed differences in expression of iron-regulating genes and levels of iron-related proteins between the retinal ganglion cells of glaucomatous and nonglaucomatous eyes, both in monkeys and in humans. Affected proteins included the iron storage, uptake, and antioxidant proteins ferritin, transferrin, and ceruloplasmin, respectively. Our findings are consistent with the conclusions of these previous studies that the regulation of iron and the response to oxidative stress may play important roles in glaucoma pathogenesis by impacting aqueous humor outflow and/or retinal ganglion cell survival.
The role of calcium homeostasis in glaucoma and other neurodegenerative diseases, as well as aging, has also been studied. Influx and intracellular accumulation of high levels of calcium is known to trigger cell death through caspase-dependent degradation.7
Furthermore, aging causes subtle changes in calcium homeostasis through mitochondrial dysfunction that renders neurons more vulnerable to oxidative stress.6
A background of age-related calcium dysregulation combined with environmental or genetic stressors has been hypothesized to be associated with neurodegenerative diseases.6
For example, Alzheimer's Disease (AD) research suggests that there is a positive feedback loop between calcium dysregulation and production of toxic amyloid-β, resulting in neuronal death.6
Research in Parkinson's Disease (PD) has also suggested that calcium dysregulation drives neuronal loss, with relationships demonstrated between α-synuclein aggregates and calcium dysregulation in sporadic PD15–17
and results indicating that higher levels of calcium-buffering proteins confer resistance to degeneration among dopaminergic neurons.18–20
Finally, calcium dysregulation and overload have been identified in both TM8
and lamina cribrosa cells.9
Considering the common neurodegenerative features between AD, PD, and glaucoma and a possible epidemiologic association between these three diseases,21–26
it would not be surprising if calcium dysregulation were found to increase the risk of glaucoma.
We acknowledge that our study conclusions are limited by the reliance on a self-report of a prior diagnosis of glaucoma that may be subject to recall bias and disease misclassification. One must consider the possibility that there is an association between supplemental oxidant consumption status and misclassification of glaucoma and that such a potential differential bias may amplify our results away from the null hypothesis, particularly if high consumers of iron or calcium supplements are more likely to self-report glaucoma. In ideal circumstances, self-reported glaucoma should be confirmed or refuted by complete ophthalmic examination including structural and functional assessment of optic nerve status; lack of such testing leaves open the possibility that some subjects who self-report a diagnosis of glaucoma are in fact glaucoma suspects or ocular hypertensives. However, there is no compelling reason to believe that individuals taking a high level of supplementary oxidants would be systematically more or less likely to accurately recall a glaucoma diagnosis than would those taking lower levels of such supplements. If recall and misclassification with regard to glaucoma diagnosis is nondifferential among those consuming high and low levels of oxidants, as well as among those not using such supplements, one would expect the results to be biased toward the null, with resultant underestimation of the strength of the relationship between such consumption and glaucoma diagnosis.
An additional limitation of our study was the ascertainment of supplement intake information based on 30-day recall, which included both subjects who had been on long-term supplementation and those who had only recently begun receiving calcium or iron supplements. Furthermore, nutrient intake was aggregated only from supplement and antacid use and did not take into account natural dietary sources. However, dietary supplements are known to contribute substantially to the total intake of calcium and iron in the United States, particularly in elderly women.27
There is also no compelling reason to suspect that these limitations in the measurement of supplemental oxidant intake would bias our results by differentially impacting subjects based on glaucoma status.
Much additional research elucidating the link between glaucoma and oxidant intake is required before we can advocate that patients discontinue supplemental calcium or iron therapy, particularly if such supplementation is necessary for a medical condition such as iron-deficiency anemia. As is the case with most population-based studies, our results do not shed light on the mechanism by which oxidant intake may increase the risk of glaucoma. Intraocular pressure measurements were not available, and their absence limited our ability to further hypothesize regarding the effects of calcium and iron intake on the TM outflow pathway. In addition, an association found in a cross-sectional study cannot determine the direction of causation; therefore, one must at least consider the possibility that a diagnosis of glaucoma could have led to increased calcium and/or iron supplementation. However, this scenario is unlikely, given that oxidant supplementation is generally used for the treatment of other clinical entities and is not recognized as an effective therapy for glaucoma.
Finally, one cannot rule out the possibility that the association we found between glaucoma and supplementation of calcium or iron actually represents a relationship between glaucoma and deficiency of calcium or iron. Iron deficiency, the surrogate for which may be recent treatment of anemia, was not a significant confounder and therefore was not included in the final model. Calcium deficiency as represented by a reported diagnosis of osteoporosis was significantly different between those with and without glaucoma on crude comparison, but this may be due to the age differences between the two groups. Osteoporosis was a significant confounder that was adjusted for in the multivariate model. It is also noteworthy that neither calcium nor iron deficiency is a proven risk factor for glaucoma and there is presently no plausible biologic mechanism that can support such a hypothesized association.
In summary, we found that after adjustment for confounding demographic factors, comorbidities, and health-related behaviors, consumption of supplementary calcium ≥800 mg/d or supplementary iron ≥18 mg/d was associated with significantly greater odds of self-reported glaucoma than was no supplementary consumption of these oxidants. There may be a threshold level above which consumption of calcium or iron influences glaucoma, whereas consumption of these oxidants at lower levels has no such effect. The more than sevenfold greater odds of a glaucoma diagnosis in those with high levels of calcium and iron supplementation strongly suggest an important association that warrants further study. In addition to epidemiologic confirmation of our findings, further research is needed to determine whether calcium and iron intake may increase the risk of glaucoma progression and to elucidate the potential mechanisms by which consumption of these oxidants may influence glaucoma pathogenesis.