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T 14: The Conundrum of Fracture Risk in Users of Proton Pump Inhibitors: A Retrospective Analysis
Associate Medical Director
Robarts Clinical Trials Inc./ University of Western Ontario Canada
Provide an overview of fracture risk data associated with PPIs; Investigate the pattern of publications related to the topic; Outline future studies aimed to solve the conundrum.
The study was conducted at the U.S. FDA. Relevant materials were gathered by: (1) Literature review of fracture risk encountered with PPI use; (2) Evaluation of FAERS data; (3) Computation and analysis of PRRs.
The second author information: Edward D Bashaw, PharmD.
This project was supported in part by an appointment to the research participation program at the Center of Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration.
40 articles were selected for being directly relevant to fracture risk in PPI users. Animal and in vitro studies started to appear in the scientific literature since 1998, human – since 2005. The number of publications varied from 1 to 9 per year, and increased over time. 24 studies evaluated the association between fracture risk and PPI intake. 22 out of 24 found a small statistically increased risk of fracture (OR, range 1-2). The increase in risk was found across different countries, study types, age groups. However, the results were inconsistent across these studies for a dose- or a duration-response, or time-to-onset of fracture. Many of the studies were population-based and of large size. However these studies were observational and prone to residual confounding. None of the studies reported on fatalities associated with fractures, none - accounted for OTC drug use for PPIs. 7 studies evaluated BMD in PPI users. 4 out of 7 showed a small decrease in BMD in PPI users compared to non-users. Animal studies indirectly supported epidemiological data. Cumulative PRRs showed a marginal drug-event association.
Plausible biologic mechanisms: (1) PPIs could affect osteoclasts by inhibiting the osteoclastic proton pump; (2) Chronic PPI exposure increase gastrin levels resulting in stimulation of osteoclasts by histamine and blockade of osteoclast H1 receptors by H1RAs which reduces bone resorption by mature osteoclasts; (3) Without an appropriate acid environment, Ca may be retained in food reducing its absorption/leading to compensatory secondary hyperparathyroidism which may increase the rate of osteoclastic bone resorption; (4) PPIs suppression of gastric acid secretion lowers folate/vitamin B12 absorption leading to alterations in homocysteine levels that may contribute to increased fracture risk; (5) Dizziness/confusion as side effects of PPIs may increase the likelihood of falls. Overprescribing and long term PPI use are plausable explanation.
The long-term safety issues such as an increased fracture risk in PPI users cannot be excluded. Overprescribing and long-term PPI use that was not considered in the original risk-benefit approval “metric” are plausible explanations, though no definite conclusion can be drawn from the studies conducted so far. Future studies evaluating the change in PPIs prescription pattern over time are needed. The ability to do these studies will be hampered by the expected exiting of the marketplace by innovator companies once marketing becomes economically less viable. In such situations, the lodging of the data in a university consortia or in a “safe harbor” may be necessary to ensure the ability of such long term evaluations to be made.