Fracture Risk and Bone Mineral Density Reduction Associated with Proton Pump Inhibitors

Yuen Ting Lau, Pharm.D.; Nasiya N. Ahmed, M.D.


Pharmacotherapy. 2012;32(1):67-79. 

In This Article

Potential Mechanisms of Proton Pump Inhibitor-related Fracture

The acidic environment in the stomach facilitates dissolution and absorption of insoluble calcium salts;[25,26] therefore, the reduction in calcium absorption and the resultant decrease in BMD have been the proposed explanation for the association between PPIs and fracture. Some studies have demonstrated that PPIs decrease calcium absorption from food or calcium supplements. Reduced calcium absorption has also been associated with an increased risk of hip or vertebral fracture in postmenopausal women.[27–30] On the contrary, our review on the current data did not find changes in baseline BMD or subsequent BMD associated with PPIs.[11,12,18] Likewise, most studies on the risk of fracture associated with histamine2-receptor blockers, which also suppress gastric acid secretion, did not find changes in BMD in users of these agents compared with nonusers.[11,12,31] Other investigators have also reported that calcium absorption from food in healthy subjects or postmenopausal women is not affected by short-term (≤30 days) omeprazole therapy.[32,33]

The mechanism of PPI-related fracture may be related to the other factors that determine bone strength, including bone geometry, trabecular bone composition, and microarchitecture, by affecting the bone remodeling process. The PPIs may affect bone remodeling and repair by reducing bone resorption by inhibiting the vacuolar H+-ATPase located on the ruffled border of the osteoclasts.[34,35] The vacuolar H+-ATPase releases protons to acidify the extracellular matrix in the resorbing lacuna, allowing the solubilization of hydroxyapatite and the activation of proteolytic enzymes.[36–38] Whether the inhibition of the vacuolar H+-ATPase by PPIs is clinically relevant is questionable since this inhibition requires a 100-fold higher concentration of omeprazole than the inhibition of the parietal H+,K+-ATPase.[39] Studies that investigate biomarkers of bone remodeling or radiographic studies on the microarchitecture of the bone can provide further insight into the effects of PPIs on bone health.