Elsevier

Bone

Volume 57, Issue 2, December 2013, Pages 437-442
Bone

Original Full Length Article
Use of proton pump inhibitors is associated with lower trabecular bone density in older individuals

https://doi.org/10.1016/j.bone.2013.09.014Get rights and content

Highlights

  • InCHIANTI study evaluates risk factors for mobility-disability in the elderly.

  • pQCT and medications were analyzed in 1038 older men and women.

  • Difference in bone density and geometry were analyzed in PPI users and nonusers.

  • Trabecular bone density is lower in older PPI users than in nonusers.

Abstract

Proton pump inhibitors (PPIs) are highly effective in the treatment of upper gastrointestinal acid-related conditions and are fast becoming one of the most frequently prescribed treatments in adult or older persons. Recent data show that long-term use of PPIs in older subjects is associated with important undesirable effects, including a higher risk of osteoporotic fractures. The mechanisms of this association are unclear and the relationship between the use of PPIs and parameters of bone mass and geometry has never been fully explored.

This study investigates the relationship between the chronic use of PPIs and the parameters of bone mass (cortical and trabecular bone mineral density — vBMDc and vBMDt) and bone geometry (cortical and trabecular cross sectional area — tCSA and cCSA) in older individuals.

The study population consisted of 1038 subjects (452 men and 586 women) 65 years or older, selected from the InCHIANTI study, with complete information on computerized tomography performed at tibial level (pQCT) and on medications. Participants were classified as PPI users and nonusers based on self-report of PPI use over the last 15 days, with PPI users (36 subjects, 14 men and 22 women) making up 3.4% of the study population (mean age 75.7 ± 7.4 years). The relationship between use of PPIs and pQCT bone parameters was tested by multivariate linear regression analysis adjusted for age, sex and several clinical factors and/or statistically confounding variables identified by partial correlation coefficient and Spearman partial rank order correlation coefficients, as appropriate (age, sex, BMI, caloric intake, IGF-1, IL-6, calcium, estradiol, bioavailable testosterone, vitamin D, parathyroid hormone, cross-sectional muscle area, and level of physical activity). PPI users showed age- and sex-adjusted lower vBMDt than nonusers (180.5 ± 54.8 vs. 207.9 ± 59.4, p = 0.001). The inverse association between PPI use and vBMDt remained almost unchanged after adjustment for multiple confounders. There was no statistically significant difference in vBMDc, tCSA and cCSA between PPI users and nonusers.

In community dwelling older persons, the use of PPIs is inversely associated with vBMDt, an early marker of the osteoporotic process. These findings suggest that PPI use might increase the risk of fractures in older subjects through its detrimental effects on trabecular bone.

Introduction

Proton pump inhibitors (PPIs) are potent gastric acid suppressing drugs with proven efficacy both in the prevention and treatment of peptic ulcers, gastroesophageal reflux disease, and erosive esophagitis [1], [2]. Since their introduction in the 1980s, PPIs have been one of the most prescribed classes of drugs worldwide due to their high effectiveness in acid-related conditions, compared to histamine receptor antagonists [3].

In the last two decades we have observed a marked increase in PPI use, especially among older persons, supported by the availability of both over-the-counter and generic formulations [4].

Despite the evident clinical benefits, recent epidemiological studies underline an often inappropriate PPI prescription for up to 50–80% of patients admitted to acute wards of geriatric and internal medicine [5], [6], [7], [8], [9], [10].

There is growing evidence that high PPI exposure and/or an inappropriate treatment period are accompanied by a variety of relevant clinical adverse events. This is particularly evident in chronic PPI users and vulnerable classes of individuals such as the elderly. In this population the chronic acid suppression induced by PPIs has been associated with an increased risk of community-acquired pneumonia [11], [12], [13], [14], C. difficile infections [15], [16], [17], and malnutrition [18] including hypomagnesemia [19]. In addition, PPIs share common metabolic pathways with several classes of medications such as nonsteroidal anti-inflammatory, antiplatelet and bisphosphonates, whose effectiveness might be reduced by PPI use [20], [21]. More recently, in older patients discharged from acute care hospitals, the use of high doses of PPIs has been associated with an increased risk of 1-year mortality [22].

The Food and Drug Administration has recently reported in a safety communication the evidence of a worrying increased risk of fractures induced by chronic PPI treatment [23]. A meta-analysis of 11 observational studies showed a mild increased risk of hip and vertebral fractures in PPI users of both sexes, compared to H2RA users [24]. Interestingly, the results were stronger in older participants and confirmed in a recent meta-analysis [24], [25].

Age-related changes in bone mass, bone mineral density (BMD), bone geometry and architecture, cortical bone thickness and trabecular porosity, negatively affect the bone strength, one of the most important determinants of fractures. Bone remodelling is faster and significantly more evident in trabecular bone and as far as we know, changes in trabecular bone occur early in the pathway to full blown osteoporosis [26], [27]. Use of PPIs might exacerbate the age related modifications in bone density and strength.

Despite the increasing evidence of a relationship between PPI and bone fractures, few studies have explored the hypothesis that PPI use may be associated with deteriorated bone density and structural geometry.

The aim of the study is to characterize the relationship between PPI use and parameters of bone mineral density and geometry as well as markers of bone strength in older community dwelling persons.

Section snippets

Study population

InCHIANTI is an epidemiological study of risk factors for mobility disability in the elderly, designed by the Laboratory of Clinical Epidemiology of the Italian Research Council of Aging (Florence), and conducted on a representative sample of a population living in Greve in Chianti and Bagno a Ripoli, two small towns of Tuscany, Italy. The study design and data collection have been described elsewhere [26], [27], [28], [29]. Of the whole study population, 1260 subjects were 65 years old or

Results

The characteristics of the participants were presented for the entire sample and participants were stratified according to PPI use. The prevalence of PPI use among the InChianti community dwelling older persons was 3.4% (22 women and 14 men). The majority of persons were on PPI (N = 25; 70%) due to gastro-protection during NSAIDs or chronic aspirin treatment; the remaining 30% (N = 11) were on PPI because of peptic gastro-intestinal ulcer (Table 1). Since the neither interaction terms sex*PPI

Discussion

Our data show a negative association between PPI use and trabecular bone mineral density in a small sample of community dwelling older persons. These findings support the hypothesis of a possible direct effect of PPIs on bone mineral metabolism.

This is the first study testing the relationship between PPI use and parameters of bone mass and geometry in older persons. Several studies have shown a significant association between PPI use and bone fractures [24], [25], although the number of

Authors' roles

Study design was performed by M.M. and F.L.; study conduct, by F.L., S.B., A.C., F.L. and L.F.; data collection, by F.L., S.B., A.C. and F.L.; data analysis, by M.M. and F.L.; data interpretation, by G.C., M.M., F.L., C.C., C.R., A.N. and T.M.; drafting the article, by M.M., F.D. and G.B.; revising the article content, by M.M. and L.F.; and approving the final version of the article, by M.M., G.C., T.M., S.B., A.C., C.R., F.L. and L.F.

Disclosure

All authors state that they have no conflicts of interest.

Acknowledgments

The InCHIANTI Study was supported as a “targeted project” (ICS 110.1/RS97.71) by the Italian Ministry of Health and in part by the US National Institute on Aging (Contracts N01-AG-916413 and N01-AG-821336), and by the Intramural Research Program of the US National Institute on Aging (Contracts 263 MD 9164 13 and 263 MD 821336) and by grant RF-2010-2312659 from the Italian Ministry of Health and Emilia Romagna Region. None of the sponsoring institutions interfered with the collection, analysis,

References (52)

  • A. Pilotto et al.

    Clinical features of reflux esophagitis in older people: a study of 840 consecutive patients

    J Am Geriatr Soc

    (2006)
  • D.L. Bhatt et al.

    American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents

    Circulation

    (2008)
  • J.N. Bashford et al.

    Why are patients prescribed proton pump inhibitors? Retrospective analysis of link between morbidity and prescribing in the General Practice Research Database

    BMJ

    (1998)
  • D.M. McCarthy

    Adverse effects of proton pump inhibitor drugs: clues and conclusions

    Curr Opin Gastroenterol

    (2010)
  • I. Forgacs et al.

    Overprescribing proton pump inhibitors

    BMJ

    (2008)
  • M. Naunton et al.

    Overuse of proton pump inhibitors

    J Clin Pharm Ther

    (2000)
  • A.Z. Mat Saad et al.

    Proton pump inhibitors: a survey of prescribing in an Irish general hospitalì

    Int J Clin Pract

    (2005)
  • N.M. Walker et al.

    An evaluation of the use of proton pump inhibitors

    Pharm World Sci

    (2001)
  • K. Grant et al.

    Continuation of proton pump inhibitors from hospital to community

    Pharm World Sci

    (2006)
  • R.J. Laheij et al.

    Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs

    JAMA

    (2004)
  • L.A. Rodríguez et al.

    Acid-suppressive drugs and community-acquired pneumonia

    Epidemiology

    (2009)
  • N. Sultan et al.

    Association between proton pump inhibitors and respiratory infections: a systematic review and meta-analysis of clinical trials

    Can J Gastroenterol

    (2008)
  • J. Johnstone et al.

    Meta-analysis: proton pump inhibitor use and the risk of community-acquired pneumonia

    Aliment Pharmacol Ther

    (2010)
  • C. Bavishi et al.

    Systematic review: the use of proton pump inhibitors and increased susceptibility to enteric infection

    Aliment Pharmacol Ther

    (2011)
  • M.D. Howell et al.

    Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection

    Arch Intern Med

    (2010)
  • A. Linsky et al.

    Proton pump inhibitors and risk for recurrent Clostridium difficile infection

    Arch Intern Med

    (2010)
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