Nutritional Consequences of Long-term Acid Suppression; Are They Clinically Important?

David A. Johnson


Curr Opin Gastroenterol. 2016;32(2):136-140. 

In This Article


Among the more pressing concerns for prolonged PPI use is the potential for an increased risk of osteoporosis and osteoporosis-related fractures, which carry with them significant morbidity and mortality. Calcium serves an important role in bone health and formation, as it is a key component of hydroxyapatite (the main structural element of bone). The hypothesis for the mechanism of PPI-induced bone fractures is that dietary calcium absorption is dependent on an acidic environment in the gastrointestinal tract. Owing to the decrease in acidity from the pharmacologic effect of PPIs, a potential loss of calcium absorption occurs. This reduction in calcium absorption leads to decreased osteoclastic activity and thus potentially decreases in bone mineral density, thereby increasing fracture risk.[22,23] In 2010, the FDA released a safety announcement concerning the potential for an increased risk of fractures among PPI users.[24] Although this statement was later revised to limit the risk for PPI use longer than a short-term 2-week treatment course,[24] this topic continues to be raised by healthcare providers and patients.

The pathophysiological basis of this association is multifactorial. First, gastric acid plays an essential role in the absorption of dietary calcium, which is consumed in the form of insoluble calcium salts and dependent on the acidic environment of the gastrointestinal tract to release soluble ionized calcium.[25] Therefore, hypochlorhydric states induced by PPIs could lead to impaired calcium absorption. Second, this impaired absorption of calcium may lead to a compensatory secondary hyperparathyroidism, thereby increasing the rates of osteoclastic bone resorption. Last, PPIs have been shown to directly inhibit osteoclast activity by inhibiting the vacuolar H+/K+ ATPase (proton pump).[26] Overall, the regulation of calcium metabolism and its relation to bone homeostasis is multifactorial and complexly regulated.

Case-control studies have suggested a weak association between prolonged PPI use and increased bone fracture risk, although the magnitude of the ORs is low (<2) in all of these studies.[25,27,28] Furthermore, these studies are subject to confounding variables that may bias results. PPI use for up to 5 years has not been associated with osteoporosis, even at a high dose,[29] and marginally affects 3-year bone mineral density of the hip in postmenopausal women.[30] When specifically examined, PPI and bone fracture events, adjusting for other key independent risk factors (e.g., alcohol abuse, arthritis, diabetes, kidney disease, glucocorticoids, cerebrovascular disease, dementia, epilepsy, visual impairment, anxiolytics, and preexisting osteoporosis), showed no increase in fracture.[31,32] The most recent longitudinal follow-up, which comes from the previously cited 5-year comparative prospective trial of surgery versus PPI therapy for GERD, showed no sequential changes in serum calcium[7] (Fig. 4).

Figure 4.

Serial serum calcium levels: gastroesophageal reflux disease treatment (SOPRAN/LOTUS studies) [7].

Evidence Summary

In summary, chronic PPI use is not associated with increased osteoporosis risk or accelerated bone mineral density loss, and any association between PPI use and hip fractures is likely related to other independent risk factors for osteoporosis. There are excellent longitudinal long-term data to support this conclusion. Increased bone density monitoring or use of supplemental calcium for patients taking PPIs is not recommended unless warranted for other clinical indications.