Proton Pump Inhibitors but Not H2RAs Linked to Fracture Risk

Laurie Barclay, MD

May 10, 2011

May 10, 2011 — Proton pump inhibitor (PPI) use is linked to fracture risk, according to the results of a meta-analysis reported in the May/June issue of the Annals of Family Medicine.

"[PPIs] and histamine 2 receptor antagonists (H2RAs) are the most popular [acid-suppressive drugs] available, and millions of individuals currently take these medications on a continuous or long-term basis," write Chun-Sick Eom, MD, MPH, from Seoul National University Hospital, Republic of Korea, and colleagues. "These potent drugs are used to treat various disorders, and indications for long-term maintenance therapy with this drug class continue to expand. The relationship between [acid-suppressive drug] use and bone health remains unclear."

Using common keywords, the reviewers searched MEDLINE (PubMed), EMBASE, and the Cochrane Library databases from their beginnings through December 2010. Selection criteria were case-control, nested case-control, and cohort study designs. The articles were independently reviewed and selected by 2 investigators. Heterogeneity in the included articles necessitated use of random effects meta-analysis to arrive at pooled effect estimates.

The final analyses included 5 case-control studies, 3 nested case-control studies, and 3 cohort studies selected from 1809 articles meeting the initial inclusion criteria. With use vs nonuse of PPIs, the pooled odds ratio (OR) for fracture was 1.29 (95% confidence interval [CI], 1.18 - 1.41) compared with 1.10 (95% CI, 0.99 - 1.23) for use vs nonuse of H2RAs.

Risk for any fracture and for hip fracture was increased with long-term use of PPIs (adjusted OR, 1.30 [95% CI, 1.15 - 1.48]; adjusted OR, 1.34 [95% CI, 1.09 - 1.66], respectively). Vertebral fracture risk was also increased by 54% with PPI use. In contrast, long-term use of H2RA was not significantly associated with fracture risk.

"We found possible evidence linking PPI use to an increased risk of fracture, but no association between H2RA use and fracture risk," the study authors write. "Widespread use of PPIs with the potential risk of fracture is of great importance to public health. Clinicians should carefully consider their decision to prescribe PPIs for patients already having an elevated risk of fracture because of age or other factors."

Limitations of this study include possible uncontrolled confounding. The study authors therefore recommend further prospective studies including large randomized controlled trials with long follow-up.

"It is not necessary to treat patients to the point of an achlorhydric state to resolve acid reflux symptoms, so we recommend that drug doses be chosen thoughtfully with consideration of what is necessary to achieve desired therapeutic goals," the study authors conclude.

In an accompanying editorial, James M. Gill, MD, MPH, from Delaware Valley Outcomes Research in Wilmington, and colleagues discuss balancing risks and benefits of PPIs.

"PPIs have clear benefits in patients that require them, and they should not be denied to patients who are likely to benefit from them," the editorialists write. "On the other hand, long-term PPI exposure may lead to other unwanted effects and should be reserved for patients likely to benefit from them. They should not be used long-term for undifferentiated dyspepsia, but neither should they be denied for patients with established persistent [gastroesophageal reflux disease], [nonsteroidal anti-inflammatory drugs] risk, and hypersecretory states, while aiming for the lowest effective maintenance dose."

A National Research Foundation of Korea Grant funded by the Korean government supported this study. The study authors and editorialists have disclosed no relevant financial relationships.

Ann Fam Med. 2011;9:257-267, 200-202. Full text