The PPI Paradox

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Millions of people take long-term proton pump inhibitors for acid-related GI complaints. These agents are very effective and appear to have an excellent safety profile. However, they may also have interesting effects on calcium and phosphate balance that I recently became aware of.
PPIs act via inhibition of the parietal cell H+/K+ ATPase, producing an ‘inhibitory complex’ which blocks HCl secretion and results in loss of the normal acidic environment of the upper GI tract. Ordinarily, this acidic milieu facilitates the release of ionized calcium from insoluble calcium salts, improving calcium solubility, which is necessary for its absorption. Reduced absorption of calcium is believed to explain the increased rates of osteopenia and fracture seen in medical states associated with achlorhydria, such as pernicious anemia and post-gastrectomy. Furthermore, several studies show that long-term PPI therapy, particularly at high doses, is associated with an increased risk of hip fracture. Also, long-term PPI use can lead to hypomagnesemia with a low fractional excretion of Mg, suggesting a similar mechanism may be responsible.
Based on these observations, I began to wonder if PPIs would decrease the efficacy of calcium-based phosphate binders, via a reduction in the ionized fraction available to bind phosphate in the gut. There is almost nothing written on this, apart from a single, small, prospective Japanese study that did indeed show that acid suppression significantly reduced the phosphorus binding ability of calcium carbonate, resulting in impaired phosphate control in hemodialysis patients.
Then, just to keep things interesting, I found another study that suggests that PPIs may have the opposite effect when given with non-calcium containing binders. In a retrospective analysis of 108 HD patients, more patients taking a PPI plus a phosphate binder achieved phosphorus control, defined as an average phosphorus level below 6 mg/dL and “a calcium × phosphate product level less than 55, than did those taking only a phosphate binder (76% vs 24%; P = .001). However, the benefits were only observed in those taking sevelamer; these authors did not replicate the findings from the aforementioned study from Japan. The mechanism behind this observation are not known.
So there you have it: there is a suggestion from this rudimentary evidence that PPIs may potentially impair phosphate control when given with calcium-containing binders, but paradoxically improve control when given with non-calcium containing binders. This could form the kernel of an interesting clinical study…


  1. my thoughts exactly, conall. very interesting.

  2. I have seen a patient that normalized her phosphate after she started taking PPI in addition to renvela. prior to that renvela was not effective. I have been wondering as well.

  3. Thanks Michael, have updated the piece to mention hypomagnesemia… I wonder if the mechanism is the same?

  4. seeing a lot of PPI-induced hypomagnesium too.

  5. Interesting angle, thanks for feedback! Do you have a reference?

  6. Some evidence exist that PPI may disrupt the acidic environment needed for the osteoclast function of bone resorption and modelling, maybe weakening the bone and increasing the risk of fractures.

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