In May of 2010, the FDA made a troubling announcement: some of the world’s most popular drugs may increase the risk of hip, wrist and spine fractures.
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The agency’s warning covered a staggering roster of pharmaceuticals, all of which were designed to treat gastroesophageal reflux disease (GERD), stomach and intestinal ulcers, esophageal inflammation and, in some cases, frequent heartburn. In all, the FDA listed 11 different drugs:
While most of these drugs contain different active ingredients, they all share one thing in common: their mechanism of action. Each of these products is a “proton pump inhibitor,” a chemical that short-circuits the secretion of gastric acids.
In 2013, around 15 million US patients were being prescribed proton pump inhibitors. That estimate is likely to be low, however, since many PPIs are now available over-the-counter. But you won’t see the FDA warning on over-the-counter proton pump inhibitors, like Nexium 24HR or even the aforementioned Prilosec OTC. Why?
These over-the-counter products are intended as a short-term treatment for heartburn. As Nexium 24HR’s packaging makes clear, the drug shouldn’t be taken “for more than 14 days or more often than every 4 months.” In its data review, the FDA concluded that short, intermittent treatment regimens probably don’t increase a patient’s risk of fracture. As Joyce Korvick, an FDA official, told reporters:
“epidemiology studies suggest a possible increased risk of bone fractures with the use of proton pump inhibitors for one year or longer, or at high doses. Because these products are used by a great number of people, it’s important for the public to be aware of this possible increased risk and, when prescribing proton pump inhibitors, health care professionals should consider whether a lower dose or shorter duration of therapy would adequately treat the patient’s condition.”
In 2006, Danish researchers published what is quite possibly the first study to look into the fracture risks of common antacids. Surprisingly, H2 receptor antagonists like Pepcid were associated with a decrease in the risk of broken bones. Patients who took drugs that work like Pepcid were around 12% less likely to break bones than members of the general population. Proton pump inhibitors, though, significantly increased the risk of fracture, intensifying the danger by:
While the results were limited, the Danish study sparked a wave of interest in proton pump inhibitors.
Later the same year, a group from the University of Pennsylvania used data from UK patients with broken hips to investigate the link further. Most importantly, the researchers took time into account, measuring how the fracture risk changed between patients who took proton pump inhibitors for different lengths of treatment:
This kind of relationship, in which risk increases along with length of exposure, is precisely what one would expect if proton pump inhibitors do, in fact, cause a decrease in bone integrity. As a result, the study’s authors came to a simple conclusion: “long-term PPI therapy, particularly at high doses, is associated with an increased risk of hip fracture.”
But even at this early stage of research, the scientists were able to propose a theory explaining the association: “proton pump inhibitors (PPIs) may interfere with calcium absorption.”
This idea is pretty simple when you consider why stomach acid is so important to human health. Gastric acids help our bodies break down food, unlocking the vital nutrients and minerals locked inside. One of those minerals, calcium, is essential to both bone development and maintenance. But because PPIs lower the amount of gastric acid in a patient’s stomach, the drugs may also decrease the total amount of calcium that can be used to strengthen bones. That could be why PPI patients seem more likely to break bones than other people, the researchers suggested.
On the other hand, proton pump inhibitors also appear to inhibit the process of “bone resorption,” in which bones are naturally broken down to unlock minerals. This complicates the picture somewhat, since it’s possible that preventing bone decay could balance out the effect proton pump inhibitors may have on our ability to absorb calcium.
Another complication? Medical evidence. In a 2010 study published in the Archives of Internal Medicine, researchers at the University of Washington found that while PPI users were at a modestly increased risk for spine, forearm and wrist fractures, their bone mineral densities (BMD) weren’t outside the norm. Bone mineral densities were slightly lower at the hip, but this effect was considered “marginal.”
Other studies have muddied the picture even further. In 2012, a group of Canadian researchers reported the results of a 10-year study on the subject. It’s design was simple: administer three bone mineral density tests to PPI patients and non-PPI users, once at “baseline,” again after five years and finally after ten years. At baseline, PPI patients had lower bone mineral densities, apparently supporting the idea that PPI use decreases bone strength. But these lower BMDs were only observed in specific places, the femoral neck and total hip. What’s more, after five and ten years, there was no further decrease in the bone mineral density of PPI patients.
Thus we have inconsistent evidence: proton pump inhibitors might decrease bone mineral density, at least in specific places, but this decrease doesn’t seem to accelerate as people take PPIs for longer periods of time. At least for now, our understanding of the mechanism by which PPIs increase the risk of fracture has stalled. The fracture risk, however, does appear to hinge on the length of exposure in some way, although this link is complicated, too.
In a 2008 study, researchers from Winnipeg found that courses of treatment from 1 to 6 years long increased the risk of hip fractures, but didn’t change the risk for wrist or spine breaks. After five years of exposure to PPIs, a patient’s risk of breaking a hip rose by 62%, then grew to a terrifying 455% after seven or more years of use. Their risk for osteoporosis-related fractures overall also increased dramatically, by up to 92%, after seven years of proton pump inhibitor therapy.
Seven years, of course, is a very long time, especially for drugs meant to be taken for short periods of time. Even prescription PPIs are only intended to be used for up to eight weeks at a time. The risk of fracture, then, would seem to be very low, since it only increases after many years of exposure.
A study in 2010 lowered this risk “threshold” from seven years to two years. Researchers at Kaiser Permanente found that people who had broken hips were more likely than their peers to have been prescribed a proton pump inhibitor for two or more years previous to their accident. Tellingly, the risk grew even higher at larger PPI doses and decreased after patients were taken off the drugs. But while the risk jumped after two years of use, this was only true for patients who were already at risk of a hip fracture due to some other factor. Patients without coincident risk factors seemed to elude the increased risk associated with proton pump inhibitors. In other words, PPI use may be compounding other problems, rather than weakening bones on its own.
There’s another, more practical, problem to this logic, and it’s one of which the FDA is well aware. Proton pump inhibitors are frequently misprescribed. In a 2014 report on the topic, FDA researcher Tamara Johnson, MD noted how many doctors are prescribing PPIs for unapproved uses “and / or for longer periods of time than initially labeled.” Thus, for many patients, short-term use has bled into long-term use, along with all of its attendant risks.
Continue Reading: Proton Pump Inhibitors May Increase Risk Of Kidney Failure