Osteoporosis and Osteoporotic Fractures Problems Related to Proton Pump Inhibitors Prolonged Use

I.Yu. Golovach


The potential negative impact on the bone with the development of osteoporosis and subsequent bone fractures is one of side effects of proton pump inhibitors administration which has been much discussed for the last decade. This review covers the latest data on the relationship between the prolonged use of proton pump inhibitors and increased risk of bone fractures. To date, three large case-control studies and one retrospective cohort study demonstrated that proton pump inhibitors treatment increases the relative risk of fractures from 1.15 (95% CI 1.10–1.20) to 1.92 (95% CI 1.16–3.18); risk of the side effect development was related to drug dose (rate of administration) and duration of exposure. New studies have further proved the existing evidence linking the use of proton pump inhibitors to development of osteoporosis. Thus, long-term use of proton pump inhibitors is recognized as an independent risk factor for osteoporotic fractures. Prolonged (more than 1 year) and high rate of administration of those drugs often results in the increased risk of fracture. However, the mechanisms of the influence remain unclear and are being studied intensively. The direct effect on the absorption of calcium or osteoblast or osteoclast function does not explain the mechanism of the effect. Suppression of the activity of vacuolar H+-ATPase during long-term treatment by high dose of proton pump inhibitors can be one of the disorders of bone metabolism mechanisms. In similar cases, such vital functions as phagocytic activity of white blood cells, bone resorption and acidification of urine can be affected. Malabsorption of vitamin B12, iron, magnesium and calcium caused by prolonged administration of proton pump inhibitors and leading to mineral deficiency might be another mechanism of osteoporosis and fractures. It is also assumed that the use of proton pump inhibitors can impede the efficiency of antiosteoporotic therapy, in particular effect of bisphosphonates thus, reducing the effectiveness of their antifracturing action. These findings suggest that physicians should better avoid the combination of proton pump inhibitors and oral bisphosphonates. Parenteral antiresorptive agents (ibandronate, zoledronic acid or denosumab) are preferable in cases of the initial pathology of the upper floors of the gastrointestinal tract or high risk for esophagitis. Currently, interaction between the intake of proton pump inhibitors and osteoporotic fractures has been identified, although the mechanisms of this association are not fully understood. Whether calcium supplements and vitamin D may reduce the risk of fractures is still unclear as well. Although an increased probability of fractures is not very high, there exists the risk of bone fractures, especially in patients who already have additional risk factors under the long and high rate of administration of proton pump inhibitors. Current studies emphasize the need for clear evidence to support this class of medicines prescription, since their long uncontrolled intake may contribute to the development of side effects, including osteoporosis and osteoporotic fractures.


proton pump inhibitors; osteoporosis; fractures; calcium absorption; bone metabolism; bone mineral density


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