Introduction
Proton Pump Inhibitors (PPIs) are a common medication to treat gastrointestinal disorders including gastroesophageal reflux disease, dyspepsia, peptic ulcer disease, and prophylaxis. The action of this type of drug is to reduce the pH of the stomach by inhibiting the activity of the acidic components of gastric juices. The drug must pass through the stomach and into the small intestine to be absorbed in order to have an effect. Therefore, PPIs are typically taken ahead of meals so that the drug is active when food reaches the stomach. PPIs are prescribed fairly often because they are well tolerated and thought to have few side effects. However, recent research has suggested that PPIs may be causing osteoporotic symptoms by decreasing bone mineral density. It is believed that while decreasing the pH of the stomach, PPIs may also be inhibiting the uptake of calcium, leading to less dense bones. In fact, “the US Food and Drug Administration has issued a black-box warning advising that PPI use may increase the risk of subsequent fracture.”1 Although it is believed that PPIs are causing a decrease in bone mineral density, other factors play into fracture risk such as other mineral deficiencies, age, and general state of health. The purpose of this review is to examine if there is a causal relationship between PPI consumption and osteoporotic risk factors. This review will also examine several confounding variables to the research question including mineral deficiencies and age.
Types of PPIs
The type of PPI taken could present differing gastrointestinal effects because each drug is made slightly different to have faintly different effects. Of the studies included in this review, three of them did not differentiate between the PPIs taken by the participants in the studies.1, 2, 3 One of the studies that did examine type of PPI included the following drugs for analysis: Omeprazole, Pantoprazole, Lansoprazole, Rabeprazole, Esomeprazole, and using a combination of these drugs at the same time.4 Of these drugs, Rabeprazole was linked with a increased use of osteoporosis medication and increased risk of fall.4 In addition, users of Esomeprazole were also found to have an increased use of osteoporosis medication.4 The other study that investigated specific types of PPIs looked at Esomeprazole, Lansoprazole, Omeprazole, and Pantoprazole.5 In conjunction with the previous study, Esomeprazole and Rabeprazole were associated with a higher rate of osteoporosis and risk of falling.5 Although only two studies analyzed the effect of certain types of PPI medications, both of these studies came to the same conclusion that Esomeprazole and Rabeprazole increased the risk of osteoporotic symptoms. Therefore, perhaps the other types of PPIs are safer than the two PPIs listed previously.
Age Observance
Osteoporosis is usually thought of only affecting “old” people. However, some studies inspected PPI use in younger populations to determine if decreased bone mineral density defies age barriers. In the studies included in this review, the age ranges were extremely varied. The inclusion criteria for one study was 25 years of age or older.1 Another study had a mean age of 78; this study was also limited to just female participants, raising some interesting questions related to just females.4 One study included all participants above the age of 18, which is perhaps too broad of an age range.3 Lastly, two studies included populations of participants aged 20 to 45 years old5 and participants between the ages of 4 and 29.2 Interestingly enough, only one study truly examined “old” people. Having such a broad age range creates issues because changes in bone activity with age cannot be as easily accounted for. Bone density increases through childhood and into early adulthood, which allows for the studies that looked at the younger populations to draw more direct correlations between PPI use and bone mineral density because there should not be an age-related decrease in bone mineral density at that point in the lives of the participants.
Osteoporosis Qualifications
Osteoporosis develops in stages; first, one develops osteopenia, then the osteopenia develops into osteoporosis. The diagnosis of osteoporosis is made by taking a bone mineral density measurement of the typical sources of osteoporotic areas: the lumbar spine, femoral neck, and total hip. These areas bear much of the body’s weight throughout life, so it makes sense to measure the density of these areas because as the body ages, the ability to bear weight because more strenuous. To measure bone mineral density, dual-energy x-ray absorptiometry (DEXA) is typically used. One of the downsides to using a DEXA scanner is the exposure to radiation; therefore, some caution should be used with this machine with those who have had previously high exposure to radiation and with young children. Of the studies in this review, two of them utilized the DEXA to measure bone mineral density of the lumbar spine, femoral neck, and total hip.1, 5 Because DEXA is the gold standard for measuring bone density, the results of these two studies may be more reliable due to the sensitivity of DEXA.
Despite DEXA being the gold standard for bone mineral density measurements, there are other ways to determine if a patient has osteoporosis or decreased bone mineral density. One study related the rate of falling as an indicator of decreased bone mineral density.2 However, many confounding variables arise with this type of measurement. First, the study found that most of the fractures within their population did not occur in the areas typically associated with osteoporotic fractures.2 Falls are also not a good indicator of osteoporosis because young children and older adults experience a higher frequency of falling due to inadequate balance. Falling in general does not always indicate that a fracture will occur either; the direction of the fall, angle of impact, and underlying fragility of the bone all play a role in determining fracture risk with a fall.2 Another study associated the prescription of osteoporosis medications with a diagnosis of osteoporosis.4 The problem with drawing this conclusion is that just because a patient was prescribed with this type of medication does not mean they are being compliant with taking the medication. In this study, the researchers did not have a method to determine whether the patients were actually taking their medications; therefore, this measure is relatively invalid. Lastly, one of the studies followed up with participants after ten years of PPI use to see if they had developed osteoporosis.3 The limitation with gathering data in this manner is the researchers could not determine a causal relationship between PPI use and osteoporosis due to a great number of confounding variables.
Other Confounding Variables
Research concerning gastrointestinal issues is difficult to maintain consistency with because of the vast differences in diet and overall health amongst populations of people. The studies included in this review did what they could to eliminate confounding variables, but despite their efforts, significant confounding variables remained. One study looked at alcohol consumption, smoking, level of education, age, physical functioning, physical activity, area of residence, body mass index, number of general practitioner consultations, and chronic conditions.4 Another accounted for a variety of diseases, medications taken besides PPIs, and calcium and vitamin D supplements.5 The other studies examined the effect of other gastrointestinal issues and how they may play a role in PPI use and osteoporosis. 1, 2, 3 One of the difficulties when investigating the effects of the confounding variables is how they are reported. Obviously, age is an objective measure. However, alcohol consumption, smoking, physical activity, and others are subjective and usually self-reported. Even if a doctor asked the patient to rate their responses on a scale, scales are different for everyone. Despite the best efforts of the researchers, the variables they attempted to control for are still indeed confounding variables. One other variable that was barely mentioned in the research was the effect of the patient’s diet. Unfortunately, there is not really a method to measure this variable, but it could be crucial in trying to determine if a relationship between PPI use and osteoporosis exists.
Physiological Effects of PPIs
As previously mentioned above, PPIs are believed to block the absorption of calcium, thus stimulating osteoclast activity to increase levels of calcium in the blood. Although PPIs may affect calcium absorption, this can be combated by increasing dietary calcium, changing when the medication is taken in relation to meals, or improving the overall diet of a patient to possibly eliminate the need for PPIs.2 In addition to calcium deficiencies, vitamin B12 deficiencies have been cited to cause abnormal collagen-crossing patterns within bone.2 The deviated patterns of collagen can increase risk of fracture. PPI usage can also lead to hyperparathyroidism, causing the parathyroid to release more parathyroid hormone than needed, leading to increased osteoclast activity.2 In addition to these effects, a dose-response relationship was found in one of the studies; in young adults, higher frequency and longer exposure to PPIs increased the risk of fracture.2
Future Research
An association between proton pump inhibitor use and decreased bone mineral density and osteoporosis currently exists. However, to move to a causal relationship, more research needs to be done. Although practically impossible, confounding variables need to be neutralized as much as possible. Some ways in which some of these variables could be offset are to control the exact dosage of PPIs, eliminate all other medications, and have the participants in a controlled environment with a controlled diet. Future research could also further isolate the various types of proton pump inhibitors to determine which types are more susceptible to inducing osteoporotic symptoms. Lastly, future research should use a DEXA scanner to determine bone mineral density, as it is the gold standard for measuring bone mineral density.
Conclusion
Proton pump inhibitors are generally prescribed for a variety of gastrointestinal ailments due to patients generally tolerating the medication and few apparent side effects. However, recent research has suggested that there may be an association between long-term PPI use and osteoporosis. Unfortunately, research cannot prove a causal relationship between PPI use and osteoporosis at this point because of many confounding variables and the use of unreliable testing measures. Future research should seek to neutralize confounding variables and use DEXA scanners to measure bone mineral density. Studies with lengthy follow-ups need to be conducted to determine if long-term usage of PPIs cause a development of osteoporosis.