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CME / CE

Proton Pump Inhibitor Therapy May Be Linked to Increased Risk for Hip Fractures

  • Authors: News Author: Laurie Barclay, MD
    CME Author: Charles Vega, MD, FAAFP
  • CME / CE Released: 12/27/2006; Reviewed and Renewed: 12/27/2007
  • THIS ACTIVITY HAS EXPIRED
  • Valid for credit through: 12/27/2008
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Target Audience and Goal Statement

This article is intended for primary care clinicians, gastroenterologists, endocrinologists, and other specialists who care for patients who use PPIs.

The goal of this activity is to provide medical news to primary care clinicians and other healthcare professionals in order to enhance patient care.

Upon completion of this activity, participants will be able to:

  • Specify a possible mechanism by which PPIs may increase the risk for fracture.
  • Identify the effects of acid-suppressing medications on the risk for hip fracture.


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Author(s)

  • Laurie Barclay, MD

    Laurie Barclay, MD is a freelance reviewer and writer for Medscape.

    Disclosures

    Disclosure: Laurie Barclay, MD has disclosed no relevant financial relationships.

CME Author(s)

  • Charles P Vega, MD

    Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine

    Disclosures

    Disclosure: Charles Vega, MD, FAAFP, has disclosed that he has received grants for educational activities from Pfizer.


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CME / CE

Proton Pump Inhibitor Therapy May Be Linked to Increased Risk for Hip Fractures

Authors: News Author: Laurie Barclay, MD CME Author: Charles Vega, MD, FAAFPFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED

CME / CE Released: 12/27/2006; Reviewed and Renewed: 12/27/2007

Valid for credit through: 12/27/2008

processing....

December 27, 2006 — Proton pump inhibitor (PPI) therapy is linked to an increased risk for hip fractures, with the highest risk in those receiving high-dose PPI therapy, according to the results of a case-control study reported in the December 27 issue of JAMA.

"Proton pump inhibitors (PPIs) may interfere with calcium absorption through induction of hypochlorhydria but they also may reduce bone resorption through inhibition of osteoclastic vacuolar proton pumps," write Yu-Xiao Yang, MD, MSCE, from the University of Pennsylvania School of Medicine in Philadelphia, and colleagues. "This study was conducted to determine whether these opposing effects of PPI therapy on bone metabolism translate into clinically important alterations in hip fracture risk in a large cohort representative of the general population."

Using the UK General Practice Research Database (1987 - 2003), the investigators studied a cohort of users of PPI therapy and nonusers of acid suppression drugs who were older than 50 years. Cases included all patients with an incident hip fracture (n = 13,556), and 135,386 controls were selected using incidence density sampling and matched for sex, index date, year of birth, and both calendar period and duration of up-to-standard follow-up before the index date. The primary endpoint was the risk for hip fractures associated with PPI use. A similar nested case-control analysis for histamine-2-receptor antagonists was also performed for comparison purposes.

The adjusted odds ratio (AOR) for hip fracture associated with more than 1 year of PPI therapy was 1.44 (95% confidence interval [CI], 1.30 - 1.59); this risk was further increased in patients prescribed long-term high-dose PPIs (AOR, 2.65; 95% CI, 1.80 - 3.90; P < .001). The strength of the association between hip fracture and PPI therapy increased with increasing duration of PPI therapy (AOR for 1 year, 1.22 [95% CI, 1.15 - 1.30]; 2 years, 1.41 [95% CI, 1.28 - 1.56]; 3 years, 1.54 [95% CI, 1.37 - 1.73]; and 4 years, 1.59 [95% CI, 1.39 - 1.80]; P < .001 for all comparisons).

"Long-term PPI therapy, particularly at high doses, is associated with an increased risk of hip fracture," the authors write. "Further studies are urgently needed to confirm our findings and clarify the underlying mechanism."

Study limitations include the potential for confounding by indication or for residual confounding by unmeasured factors, inability to define the specific mechanism(s) underlying the association between PPI therapy and the risk for fracture, lack of data on PPI use before enrollment in the database, and lack of data on over-the-counter calcium supplement use.

"At this point, physicians should be aware of this potential association when considering PPI therapy and should use the lowest effective dose for patients with appropriate indications," the authors conclude. "For elderly patients who require long-term and particularly high-dose PPI therapy, it may be prudent to reemphasize increased calcium intake, preferably from a dairy source, and coingestion of a meal when taking insoluble calcium supplements."

The American Gastroenterological Association/GlaxoSmithKline Glaxo Institute for Digestive Health Award supported this study. Some of the authors have disclosed various financial relationships with AstraZeneca, Wyeth-Ayerst Laboratories, GlaxoSmithKline, Berlex, Merck, Takeda, Roche, NPS Pharmaceuticals, Novartis Pharmaceuticals, Roche-GlaxoSmithKline, TAP Pharmaceutical Products, Altana, Santarus, Eisai, and the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases Mentored Career Development Award.

JAMA. 2006;296:2947-2953.

Clinical Context

PPIs may have multiple effects on bone, according to the authors of the current study. The less acidic gastric environment created by PPIs may impair the absorption of calcium, particularly calcium supplements. However, absorption of calcium contained in dairy products may be unaffected by PPI therapy. Moreover, PPIs may actually reduce osteoclastic activity through a direct effect.

Hip fracture may be the most severe consequence of osteoporosis. It associated with a mortality rate at 1 year of 20%. The current study explores the relationship between the use of acid-suppressing medications and the incidence of hip fracture.

Study Highlights

  • Study data were drawn from the General Practice Research Database, a broad electronic medical record of patient data from the United Kingdom. Subjects included in the present analysis had at least 1 year of follow-up in the database and were at least 50 years old. Patients with a previous history of hip fracture were excluded from study analysis.
  • The study was analyzed as a case-control comparison between subjects who sustained a hip fracture at least 1 year after enrollment in the patient database and patients without fracture. Previous research found that the database was accurate in more than 90% of cases of reporting hip fracture.
  • The main study variables were the use of PPIs and histamine-2-receptor antagonists. The risk for hip fracture associated with the use of these medications was adjusted for multiple potential confounders, including sex, age, chronic illness, and prescription medication use. However, the authors could not control for the use of the over-the-counter calcium supplements.
  • 13,556 cases of hip fracture were compared with 135,386 controls. Approximately 10% of the total study cohort had received a prescription for a PPI. The mean age of subjects was 77 years, and 80% of patients were women. Multiple chronic illnesses predicted a higher risk for hip fracture.
  • The AOR of hip fracture associated with the use of PPIs was 1.44, while the AOR associated with histamine-2-receptor antagonists was 1.23. Both of these results were statistically significant. Longer duration of PPI use increased the risk for fracture, with odds ratio of 1.22, 1.41, 1.54, and 1.59 at 1, 2, 3, and 4 years of use, respectively.
  • PPIs increased risk for fracture occurred to a greater degree in men than women.
  • Use of high-dose PPIs further increased the risk for hip fracture vs regular dosing (AORs, 2.65 and 1.40, respectively). The risk for fracture associated with regular dose PPI was similar to that associated with histamine-2-receptor antagonist therapy.
  • A separate analysis limited to subjects with gastroesophageal reflux disease failed to change the study's main findings, suggesting that gastroesophageal reflux disease itself did not have a significant impact on the risk for hip fracture.

Pearls for Practice

 

  • PPIs may impair the absorption of calcium in the gut but may also inhibit osteoclast activity.
  • The current study demonstrates that PPIs, particularly when delivered at high doses for many years, may independently increase the risk for hip fracture. PPIs at a regular dose and histamine-2-receptor antagonists also increased the risk for fracture.

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