Review
Copyright ©2011 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Methodol. Sep 26, 2011; 1(1): 15-21
Published online Sep 26, 2011. doi: 10.5662/wjm.v1.i1.15
Risk of fracture and pneumonia from acid suppressive drugs
Chun-Sick Eom, Sang-Soo Lee
Chun-Sick Eom, Department of Family Medicine, Institute for Skeletal Aging, Hallym University-Sacred Heart Hospital, Kangwondo 200-704, South Korea
Sang-Soo Lee, Institute for Skeletal Aging and Orthopedic Surgery, Infectious Disease Medical Research Center, Hallym University-Sacred Heart Hospital, Kangwondo 200-704, South Korea
Author contributions: Eom CS and Lee SS contributed equally to this paper.
Supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2011-000-6208 and 2011-001-4792)
Correspondence to: Sang-Soo Lee, MD, PhD, Professor, Director, Institute for Skeletal Aging and Orthopedic Surgery, Infectious Disease Medical Research Center, Hallym University-Sacred Heart Hospital, 153 Gyodong, Chunchonsi, Kangwondo 200-704, South Korea. totalhip@hallym.ac.kr
Telephone: +82-33-2405197 Fax: +82-33-2520177
Received: August 12, 2011
Revised: September 8, 2011
Accepted: September 19, 2011
Published online: September 26, 2011

Abstract

A recently published systematic review and meta-analysis, incorporating all relevant studies on the association of acid suppressive medications and pneumonia identified up to August 2009, revealed that for every 200 patients, treated with acid suppressive medication, one will develop pneumonia. They showed the overall risk of pneumonia was higher among people using proton pump inhibitors (PPIs) [adjusted odds ratio (OR) = 1.27, 95% CI: 1.11-1.46, I2 = 90.5%] and Histamine-2 receptor antagonists (H2RAs) (adjusted OR = 1.22, 95% CI: 1.09-1.36, I2 = 0.0%). In the randomized controlled trials, use of H2RAs was associated with an elevated risk of hospital-acquired pneumonia (relative risk 1.22, 95% CI: 1.01-1.48, I2 = 30.6%). Another meta-analysis of 11 studies published between 1997 and 2011 found that PPIs, which reduce stomach acid production, were associated with increased risk of fracture. The pooled OR for fracture was 1.29 (95% CI: 1.18-1.41) with use of PPIs and 1.10 (95% CI: 0.99-1.23) with use of H2RAs, when compared with non-use of the respective medications. Long-term use of PPIs increased the risk of any fracture (adjusted OR = 1.30, 95% CI: 1.15-1.48) and of hip fracture risk (adjusted OR = 1.34, 95% CI: 1.09-1.66), whereas long-term H2RA use was not significantly associated with fracture risk. Clinicians should carefully consider when deciding to prescribe acid-suppressive drugs, especially for patients who are already at risk for pneumonia and fracture. Since it is unnecessary to achieve an achlorhydric state in order to resolve symptoms, we recommend using the only minimum effective dose of drug required to achieve the desired therapeutic goals.

Key Words: Acid-suppressive drugs, Pneumonia, Fracture



INTRODUCTION

Recently, the medical literature has paid considerable attention to unrecognized adverse effects of commonly used medications and their potential public health impact[1,2]. Acid-suppressive drugs (ASDs), represent the second leading category of medication worldwide, with sales totalling US$26.9 billion in 2005[3]. Experts have generally viewed proton pump inhibitors (PPIs) as safe[4]. However, potential complications such as gastrointestinal neoplasia, malabsorption of nutrients and increased susceptibility to infection and fracture have caused concern[5].

Of special interest is the possibility that ASDs could increase susceptibility to respiratory infections because these drugs increase gastric pH, thus allowing bacterial colonization[6,7]. Several previous studies have shown that treatment with ASDs might be associated with an increased risk of respiratory tract infections[8] and community-acquired pneumonia in adults[6,7] and children[9]. Given the widespread use of PPIs and Histamine-2 receptor antagonists (H2RAs), clarification of the potential impact of acid-suppressive therapy on the risk of pneumonia is of great importance to public health[10].

Some findings have raised the possibility that PPIs may prevent osteoporosis and fractures. Several in vitro and animal studies have suggested that PPIs may decrease bone resorption by inhibiting osteoclastic vacuolar hydrogen potassium adenosine triphosphatase (H+/K+ ATPase) activity[11-15]. Osteoclasts possess proton pumps, which are used during the excretion of H+ ions for bone resorption. Osteoclast-selective PPIs may therefore be used as antiresorptive agents[16] with the potential of preventing fractures[17-20]. Administration of a selective inhibitor of the osteoclastic vacuolar H+/K+ ATPase prevents bone loss in ovariectomized rats, an animal model representative of postmenopausal osteoporosis[19]. However, as bone resorption is necessary for the development of normal bone microstructure, one may speculate that PPI-induced blockade of the osteoclast-associated vacuolar proton pump may actually increase fracture risk[21].

USE OF ACID-SUPPRESSIVE DRUGS AND RISK OF PNEUMONIA

A recently published systematic review and meta-analysis, which incorporated all relevant studies on the association of acid suppressive medications and pneumonia that could be identified to August 2009, showed that of every 200 inpatients treated with acid suppressive medication one will develop pneumonia. From a total of 2377 articles identified in the initial search for observational studies, the authors reviewed 60 abstracts and 18 full articles, including 8 of these articles in their final analysis. They identified 8513 randomized controlled trials, and reviewed 914 abstracts and 35 full articles, including 23 of articles and 2 bibliographies of relevant articles in the study. In summary, they included five case-control studies[6,7,10,22,23], three cohort studies[3,24,25], and 23 randomized controlled trials[26-48] in the final analysis.

Main pooled analyses

Meta-analyses on observational studies with the two types of ASD showed significant positive associations between use of PPI and risk of pneumonia [adjusted odds ratio (OR) = 1.27, 95% CI: 1.11-1.46, I2 = 90.5%] and between use of H2RA and risk of pneumonia (adjusted OR = 1.22, 95% CI: 1.09-1.36, I2 = 0.0%). Meta-analysis of randomized controlled trials examining risk of hospital-acquired pneumonia in association with use of H2RA s confirmed the findings of the observational studies (relative risk: 1.22, 95% CI: 1.01-1.48, I2 = 30.6%).

Subgroup meta-analyses

In subgroup analyses by type of pneumonia, a significant positive association was observed between use of PPIs and community- acquired pneumonia (adjusted OR = 1.34, 95% CI: 1.14-1.57, I2 = 93.6%) and between use of H2RAs and hospital-acquired pneumonia (adjusted OR = 1.24, 95% CI: 1.05-1.47, I2 = 0.0%). Subgroup analyses by dose indicated a dose-response relationship. A higher dose of PPIs was more strongly associated with pneumonia (adjusted OR = 1.52, 95% CI: 1.31-1.76, I2 = 27.5%) than the usual dose (adjusted OR = 1.37, 95% CI: 1.08-1.74, I2 = 86.5%).

Subgroup analyses by duration of exposure showed that the strength of the association between use of PPIs and risk of pneumonia decreased with longer duration of therapy before the index date (date of diagnosis of pneumonia). There were significant positive associations between risk of pneumonia and use of PPIs within 7 d before the index date (adjusted OR = 3.95, 95% CI: 2.86-5.45, I2 = 0.0%), within 30 d before the index date (adjusted OR = 1.61, 95% CI: 1.46-1.78, I2 = 30.6%) and from 30 to 180 d before the index date (adjusted OR = 1.36, 95% CI: 1.05- 1.78, I2 = 84.3%).

The risk of pneumonia was greater with the use of H2RAs within 7 d before the index date (adjusted OR = 5.21, 95% CI: 4.00-6.80, I2 not available). This risk also appeared greater with the use of these drugs within 30 d before the index date (adjusted OR = 1.49, 95% CI: 0.82- 2.72, I2 = 80.4%) and from 30 to 180 d (adjusted OR = 1.21, 95% CI: 0.94-1.56, I2 = 27.6%), although these associations were not statistically significant.

Subgroup analyses of the 23 randomized controlled trials by comparators showed a significant positive association between use of H2RAs and risk of pneumonia in studies that employed sucralfate as a control (relative risk: 1.33, 95% CI: 1.04-1.69, I2 = 24.7%). Placebo-controlled studies also indicated an overall increase in the risk of pneumonia with these drugs, but this increase was not statistically significant (relative risk: 1.09, 95% CI: 0.80-1.48, I2 = 37.9%).

The authors conducted subgroup meta-analyses of the observational studies and randomized controlled trials according to methodological quality. Among the observational studies, they observed a significant positive association for both high-quality studies (adjusted OR = 1.29, 95% CI: 1.17-1.42, I2 = 0.0%) and low-quality studies (adjusted OR = 1.15, 95% CI: 1.00-1.32, I2 = 82.1%). Among the randomized controlled trials, the risk of pneumonia appeared greater in low-quality studies (relative risk: 1.35, 95% CI: 1.10-1.67, I2 = 12.5%), whereas there was no effect among the high-quality studies (relative risk: 0.96, 95% CI: 0.65-1.43, I2 = 47.0%).

Discussion

Several lines of evidence point to the biological plausibility of these observations. Firstly, ASDs may increase the risk of pneumonia by inhibiting the secretion of gastric acid, thus allowing bacterial overgrowth and colonization in the upper alimentary tract with subsequent translocation to the lungs by aspiration[6,7,49]. Secondly, H+/ K+ ATPase is present not only in the parietal cells of the stomach, but also in the respiratory tract[50,51]. It is conceivable that use of a PPI could alter the pH of the seromucinous secretions by inhibiting this enzyme, thereby encouraging bacterial growth in the respiratory tract, which could in turn lead to increased risk of pneumonia[5]. Thirdly, in vitro studies have shown that ASDs may impair the function of neutrophils and the activity of natural killer cells[52-58].

Interestingly, the most striking increase in the risk of pneumonia in association with PPIs was observed in the first week of use. The risk of pneumonia associated with use of PPIs was attenuated, but still significant, between 30 and 180 d. Recipients of H2RAs between 30 and 180 d before the index date appeared to have an increased risk of pneumonia, although the association was not statistically significant. These findings might reflect tolerance[5]. Tolerance to H2RAs generally develops within 2 wk with repeated administration, resulting in a decline in acid suppression[59]. Another reason may be that those who are more susceptible to pneumonia become ill with this disease soon after starting ASDs, leaving fewer susceptible individuals among those using these drugs for longer periods. That is, patients who remain on the drug are those who can tolerate it, whereas those who are susceptible select themselves out of the population at risk. This depletion of susceptibility effect has been considered in other pharmacoepidemiologic studies of adverse events[60].

USE OF ACID-SUPPRESSIVE DRUGS AND RISK OF FRACTURE

A recently published meta-analysis found possible evidence linking PPI use to an increased risk of fracture, but no association between H2RA use and fracture risk. The widespread use of PPIs means that the potential risk of fracture is of great importance to public health. The authors excluded 170 duplicate articles and an additional 1621 articles that did not meet the selection criteria. They reviewed the full texts of the remaining 18 articles, eventually excluding 7 of them. The remaining 11 studies were included in the final analysis[61-67].

Main pooled analyses

The overall use of PPIs was associated with a significantly increased risk of any fracture in a random-effects model meta-analysis of 4 case-control studies, 3 nested case-control studies, and 3 cohort studies (adjusted OR = 1.29, 95% CI: 1.18-1.41, I2 = 69.8%). However, use of H2RAs was not associated with an increased fracture risk (adjusted OR = 1.10, 95% CI: 0.99-1.23, I2 = 86.3%).

Subgroup meta-analyses

A positive association between the use of PPIs and fracture risk was observed in all types, but a positive association between the use of H2RAs and fracture risk was found only when nested case-control studies were combined (adjusted OR = 1.20, 95% CI: 1.13-1.28, I2 = 0.0%) or when cohort studies were combined (adjusted OR = 1.08, 95% CI: 1.02-1.13, I2 = 0.0%). In contrast, no significant association was observed in case-control studies (adjusted OR = 1.11, 95% CI: 0.81-1.51, I2 = 85.6%).

Grouping of studies according to methodological quality showed a significantly increased fracture risk with PPI use in both high-quality studies (adjusted OR = 1.32, 95% CI: 1.18- 1.47, I2 = 63.7%) and low-quality studies (adjusted OR = 1.25, 95% CI 1.06- 1.48, I2 = 78.7%). There was also a significant positive association between H2RA use and fracture risk in high-quality studies (adjusted OR = 1.13, 95% CI: 1.05-1.21, I2 = 40.3%) but not in low-quality ones (adjusted = OR 1.09, 95% CI: 0.87-1.38, I2 = 90.6%).

Grouping studies by the number of patients showed marginally no association between PPI use and fracture risk (adjusted OR = 1.16, 95% CI: 0.98-1.38, I2 = 66.5%), but no significant association between H2RA use and fracture risk (adjusted OR = 1.11, 95% CI: 0.81- 1.51, I2 = 85.6%).

When studies were grouped by fracture outcome, the authors found a significant positive association between PPI use and hip fracture risk (adjusted OR = 1.31, 95% CI: 1.11-1.54, I2 = 88.4%) and vertebral fracture risk (adjusted OR = 1.56, 95% CI: 1.31-1.85, I2 = 6.3%), whereas there was no significant association between PPI use and the risk of other fractures, or between H2RA use and risk hip or any other fracture.

In subgroup meta-analyses by duration of use, long-term use of PPIs increased the risk of any fracture (adjusted OR = 1.30, 95% CI: 1.15-1.48) and the risk of hip fracture (adjusted OR = 1.34, 95% CI: 1.09- 1.66). There was no association between long-term use of H2RAs and either of these outcomes.

Grouping studies by dose, a significantly increased risk of hip fracture was observed for both high-dose use of PPIs (adjusted OR = 1.53, 95% CI: 1.18-1.97) and usual-dose use of PPIs (adjusted OR = 1.42, 95% CI: 1.31-1.53). In contrast, there was no association with hip fracture for either high-dose or usual-dose use of H2RAs.

Subgroup analyses by sex showed no significant association between PPI or H2RA use and hip fracture risk in men, or with hip fracture or vertebral fracture risk in women.

Discussion

In this meta-analysis of observational studies, the authors found that the use of PPIs was associated with a moderate increase in the risk of fracture compared with nonuse of PPIs, whereas no significant association was observed between H2RA use and this risk. Similarly, long-term PPI use and any dose of PPIs increased the risk of fracture in a meta-analysis of all the studies reporting duration of use and dose, whereas for H2RAs neither long-term use and nor use of any dose was significantly associated with fracture risk.

No significant association was found between use of H2RAs, which are less potent acid inhibitors than PPIs, and fracture risk. On average, H2RAs block only 70% of gastric acid production, whereas PPIs suppress acid production by up to 98%[68-70]. More prolonged exposure to H2RAs may be necessary to observe similar effects on fracture risk, although long-term use of these agents was not found to increase risk. These results suggest that H2RAs and PPIs may have differing effects on bone metabolism.

Some studies suggest that H2RAs may have antiresorptive properties[71,72] and even increase bone mineral density, which could decrease fracture risk[66]. Cimetidine also has been shown to prevent osteoclast differentiation induced by histamine[73,74]. Because of the possible mixed effects of H2RAs on bone health, data regarding long-term use of these drugs and fracture risk[63,64,66,67] or bone mineral density[75] have been inconsistent.

In contrast, PPIs have been shown to inhibit gastric proton pumps at physiological concentrations, whereas the inhibition of osteoclast and other tissue H+/K+ ATPase activity, such as osteoclast proton pumps, is much less pronounced[76]. It was, however, noted that the use of H2RAs was associated with a mild increase in fracture risk in studies having high-quality methodology (NOS score > 7) and in studies adjusting for at least 5 variables, but not in studies having low-quality methodology and adjusting for fewer than 5 variables. Further research in this area is needed.

Interestingly, the subgroup meta-analyses by the number of adjustment variables showed a significantly increased risk of fracture for both PPI and H2RA use when the data were adjusted for at least 5 variables. The results for H2RAs conflict with those of Vestergaard et al[66], who reported a statistically significant protective effect with use of these drugs for any fracture and for hip fracture. The positive association they found between H2RA use and fracture risk in studies with a high level of statistical adjustment may also be consistent with the marginal association they observed in high-quality studies (NOS score > 7).

Several potential mechanisms by which PPI therapy may lead to fractures have been identified. Firstly, the small intestine’s ability to absorb ingested calcium salts depends on pH[77,78]. Calcium solubility is believed to be important for its absorption[79], and an acidic environment in the gastrointestinal tract facilitates the release of ionized calcium from insoluble calcium salts[80]. Secondly, impaired calcium absorption might lead to compensatory secondary hyperparathyroidism, which may increase the rate of osteoclastic bone resorption. Thirdly, PPIs may interfere with the resorptive activity of osteoclasts. Without osteoclast activity, old bone cannot be replaced, predisposing patients to fractures[21,67]. However, further research is required to determine the precise effect of long-term use of PPIs on bone mineral metabolism[65].Finally, gastric parietal cells appear to have a potent endocrine role in secreting estrogens[81,82]. Atrophy of the gastric mucosa, observed in patients infected with CagA-positive Helicobacter pylori[83], reduces the number of gastric parietal cells and may decrease local production of estrogens. Estrogens produced in the stomach directly induce expression and production of ghrelin[84,85], which appears to increase bone formation by osteoblasts[86].

CONCLUSION

Clinicians should carefully consider any decision to prescribe ASDs, especially for patients who are already at risk for pneumonia[87] and fracture[88-90]. Since it is unnecessary to achieve an achlorhydric state in order to resolve symptoms, we recommend using only the minimum effective dose of the drug required to achieve desired therapeutic goals.

Footnotes

Peer reviewer: Hung-Jen Liu, DVM, PhD, Professor, Institute of Molecular Biology, National Chung Hsing University, 250, Kuo Kuang RD, Taichung 402, Taiwan, China

S- Editor Wang JL L- Editor Hughes D E- Editor Zheng XM

References
1.  Eom CS, Jeon CY, Lim JW, Cho EG, Park SM, Lee KS. Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis. CMAJ. 2011;183:310-319.  [PubMed]  [DOI]
2.  Eom CS, Park SM, Myung SK, Yun JM, Ahn JS. Use of acid-suppressive drugs and risk of fracture: a meta-analysis of observational studies. Ann Fam Med. 2011;9:257-267.  [PubMed]  [DOI]
3.  Roughead EE, Ramsay EN, Pratt NL, Ryan P, Gilbert AL. Proton-pump inhibitors and the risk of antibiotic use and hospitalisation for pneumonia. Med J Aust. 2009;190:114-116.  [PubMed]  [DOI]
4.  Vanderhoff BT, Tahboub RM. Proton pump inhibitors: an update. Am Fam Physician. 2002;66:273-280.  [PubMed]  [DOI]
5.  Savarino V, Di Mario F, Scarpignato C. Proton pump inhibitors in GORD An overview of their pharmacology, efficacy and safety. Pharmacol Res. 2009;59:135-153.  [PubMed]  [DOI]
6.  Gulmez SE, Holm A, Frederiksen H, Jensen TG, Pedersen C, Hallas J. Use of proton pump inhibitors and the risk of community-acquired pneumonia: a population-based case-control study. Arch Intern Med. 2007;167:950-955.  [PubMed]  [DOI]
7.  Laheij RJ, Sturkenboom MC, Hassing RJ, Dieleman J, Stricker BH, Jansen JB. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA. 2004;292:1955-1960.  [PubMed]  [DOI]
8.  Laheij RJ, Van Ijzendoorn MC, Janssen MJ, Jansen JB. Gastric acid-suppressive therapy and community-acquired respiratory infections. Aliment Pharmacol Ther. 2003;18:847-851.  [PubMed]  [DOI]
9.  Canani RB, Cirillo P, Roggero P, Romano C, Malamisura B, Terrin G, Passariello A, Manguso F, Morelli L, Guarino A. Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children. Pediatrics. 2006;117:e817-e820.  [PubMed]  [DOI]
10.  Sarkar M, Hennessy S, Yang YX. Proton-pump inhibitor use and the risk for community-acquired pneumonia. Ann Intern Med. 2008;149:391-398.  [PubMed]  [DOI]
11.  Sahara T, Itoh K, Debari K, Sasaki T. Specific biological functions of vacuolar-type H(+)-ATPase and lysosomal cysteine proteinase, cathepsin K, in osteoclasts. Anat Rec A Discov Mol Cell Evol Biol. 2003;270:152-161.  [PubMed]  [DOI]
12.  Sasaki T. Recent advances in the ultrastructural assessment of osteoclastic resorptive functions. Microsc Res Tech. 1996;33:182-191.  [PubMed]  [DOI]
13.  Shibata T, Amano H, Yamada S, Ohya K. Mechanisms of proton transport in isolated rat osteoclasts attached to bone. J Med Dent Sci. 2000;47:177-185.  [PubMed]  [DOI]
14.  Tuukkanen J, Väänänen HK. Omeprazole, a specific inhibitor of H+-K+-ATPase, inhibits bone resorption in vitro. Calcif Tissue Int. 1986;38:123-125.  [PubMed]  [DOI]
15.  Zaidi M. Modularity of osteoclast behaviour and "mode-specific" inhibition of osteoclast function. Biosci Rep. 1990;10:547-556.  [PubMed]  [DOI]
16.  Gagliardi S, Nadler G, Consolandi E, Parini C, Morvan M, Legave MN, Belfiore P, Zocchetti A, Clarke GD, James I. 5-(5,6-Dichloro-2-indolyl)-2-methoxy-2,4-pentadienamides: novel and selective inhibitors of the vacuolar H+-ATPase of osteoclasts with bone antiresorptive activity. J Med Chem. 1998;41:1568-1573.  [PubMed]  [DOI]
17.  Rzeszutek K, Sarraf F, Davies JE. Proton pump inhibitors control osteoclastic resorption of calcium phosphate implants and stimulate increased local reparative bone growth. J Craniofac Surg. 2003;14:301-307.  [PubMed]  [DOI]
18.  Sundquist K, Lakkakorpi P, Wallmark B, Väänänen K. Inhibition of osteoclast proton transport by bafilomycin A1 abolishes bone resorption. Biochem Biophys Res Commun. 1990;168:309-313.  [PubMed]  [DOI]
19.  Visentin L, Dodds RA, Valente M, Misiano P, Bradbeer JN, Oneta S, Liang X, Gowen M, Farina C. A selective inhibitor of the osteoclastic V-H(+)-ATPase prevents bone loss in both thyroparathyroidectomized and ovariectomized rats. J Clin Invest. 2000;106:309-318.  [PubMed]  [DOI]
20.  Xu J, Feng HT, Wang C, Yip KH, Pavlos N, Papadimitriou JM, Wood D, Zheng MH. Effects of Bafilomycin A1: an inhibitor of vacuolar H (+)-ATPases on endocytosis and apoptosis in RAW cells and RAW cell-derived osteoclasts. J Cell Biochem. 2003;88:1256-1264.  [PubMed]  [DOI]
21.  Mizunashi K, Furukawa Y, Katano K, Abe K. Effect of omeprazole, an inhibitor of H+,K(+)-ATPase, on bone resorption in humans. Calcif Tissue Int. 1993;53:21-25.  [PubMed]  [DOI]
22.  Marciniak C, Korutz AW, Lin E, Roth E, Welty L, Lovell L. Examination of selected clinical factors and medication use as risk factors for pneumonia during stroke rehabilitation: a case-control study. Am J Phys Med Rehabil. 2009;88:30-38.  [PubMed]  [DOI]
23.  Myles PR, Hubbard RB, McKeever TM, Pogson Z, Smith CJ, Gibson JE. Risk of community-acquired pneumonia and the use of statins, ace inhibitors and gastric acid suppressants: a population-based case-control study. Pharmacoepidemiol Drug Saf. 2009;18:269-275.  [PubMed]  [DOI]
24.  Beaulieu M, Williamson D, Sirois C, Lachaine J. Do proton-pump inhibitors increase the risk for nosocomial pneumonia in a medical intensive care unit? J Crit Care. 2008;23:513-518.  [PubMed]  [DOI]
25.  Herzig SJ, Howell MD, Ngo LH, Marcantonio ER. Acid-suppressive medication use and the risk for hospital-acquired pneumonia. JAMA. 2009;301:2120-2128.  [PubMed]  [DOI]
26.  Apte NM, Karnad DR, Medhekar TP, Tilve GH, Morye S, Bhave GG. Gastric colonization and pneumonia in intubated critically ill patients receiving stress ulcer prophylaxis: a randomized, controlled trial. Crit Care Med. 1992;20:590-593.  [PubMed]  [DOI]
27.  Ben-Menachem T, Fogel R, Patel RV, Touchette M, Zarowitz BJ, Hadzijahic N, Divine G, Verter J, Bresalier RS. Prophylaxis for stress-related gastric hemorrhage in the medical intensive care unit. A randomized, controlled, single-blind study. Ann Intern Med. 1994;121:568-575.  [PubMed]  [DOI]
28.  Cheadle WG, Vitale GC, Mackie CR, Cuschieri A. Prophylactic postoperative nasogastric decompression. A prospective study of its requirement and the influence of cimetidine in 200 patients. Ann Surg. 1985;202:361-366.  [PubMed]  [DOI]
29.  Cloud ML, Offen W. Continuous infusions of nizatidine are safe and effective in the treatment of intensive care unit patients at risk for stress gastritis. The Nizatidine Intensive Care Unit Study Group. Scand J Gastroenterol Suppl. 1994;206:29-34.  [PubMed]  [DOI]
30.  Cook D, Guyatt G, Marshall J, Leasa D, Fuller H, Hall R, Peters S, Rutledge F, Griffith L, McLellan A. A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. Canadian Critical Care Trials Group. N Engl J Med. 1998;338:791-797.  [PubMed]  [DOI]
31.  Driks MR, Craven DE, Celli BR, Manning M, Burke RA, Garvin GM, Kunches LM, Farber HW, Wedel SA, McCabe WR. Nosocomial pneumonia in intubated patients given sucralfate as compared with antacids or histamine type 2 blockers. The role of gastric colonization. N Engl J Med. 1987;317:1376-1382.  [PubMed]  [DOI]
32.  Eddleston JM, Vohra A, Scott P, Tooth JA, Pearson RC, McCloy RF, Morton AK, Doran BH. A comparison of the frequency of stress ulceration and secondary pneumonia in sucralfate- or ranitidine-treated intensive care unit patients. Crit Care Med. 1991;19:1491-1496.  [PubMed]  [DOI]
33.  Hanisch EW, Encke A, Naujoks F, Windolf J. A randomized, double-blind trial for stress ulcer prophylaxis shows no evidence of increased pneumonia. Am J Surg. 1998;176:453-457.  [PubMed]  [DOI]
34.  Kantorova I, Svoboda P, Scheer P, Doubek J, Rehorkova D, Bosakova H, Ochmann J. Stress ulcer prophylaxis in critically ill patients: a randomized controlled trial. Hepatogastroenterology. 2004;51:757-761.  [PubMed]  [DOI]
35.  Laggner AN, Lenz K, Base W, Druml W, Schneeweiss B, Grimm G. Prevention of upper gastrointestinal bleeding in long-term ventilated patients. Sucralfate versus ranitidine. Am J Med. 1989;86:81-84.  [PubMed]  [DOI]
36.  Maier RV, Mitchell D, Gentilello L. Optimal therapy for stress gastritis. Ann Surg. 1994;220:353-60; discussion 360-3.  [PubMed]  [DOI]
37.  Martin LF, Booth FV, Karlstadt RG, Silverstein JH, Jacobs DM, Hampsey J, Bowman SC, D'Ambrosio CA, Rockhold FW. Continuous intravenous cimetidine decreases stress-related upper gastrointestinal hemorrhage without promoting pneumonia. Crit Care Med. 1993;21:19-30.  [PubMed]  [DOI]
38.  Metz CA, Livingston DH, Smith JS, Larson GM, Wilson TH. Impact of multiple risk factors and ranitidine prophylaxis on the development of stress-related upper gastrointestinal bleeding: a prospective, multicenter, double-blind, randomized trial. The Ranitidine Head Injury Study Group. Crit Care Med. 1993;21:1844-1849.  [PubMed]  [DOI]
39.  Misra UK, Kalita J, Pandey S, Mandal SK, Srivastava M. A randomized placebo controlled trial of ranitidine versus sucralfate in patients with spontaneous intracerebral hemorrhage for prevention of gastric hemorrhage. J Neurol Sci. 2005;239:5-10.  [PubMed]  [DOI]
40.  Moesgaard F, Jensen LS, Christiansen PM, Thorlacius-Ussing O, Nielsen KT, Rasmussen NR, Bardram L, Nielsen HJ. The effect of ranitidine on postoperative infectious complications following emergency colorectal surgery: a randomized, placebo-controlled, double-blind trial. Inflamm Res. 1998;47:12-17.  [PubMed]  [DOI]
41.  Mustafa NA, Aktürk G, Ozen I, Köksal I, Erciyes N, Solak M. Acute stress bleeding prophylaxis with sucralfate versus ranitidine and incidence of secondary pneumonia in intensive care unit patients. Intensive Care Med. 1995;21:287.  [PubMed]  [DOI]
42.  O'Keefe GE, Gentilello LM, Maier RV. Incidence of infectious complications associated with the use of histamine2-receptor antagonists in critically ill trauma patients. Ann Surg. 1998;227:120-125.  [PubMed]  [DOI]
43.  Pickworth KK, Falcone RE, Hoogeboom JE, Santanello SA. Occurrence of nosocomial pneumonia in mechanically ventilated trauma patients: a comparison of sucralfate and ranitidine. Crit Care Med. 1993;21:1856-1862.  [PubMed]  [DOI]
44.  Prod'hom G, Leuenberger P, Koerfer J, Blum A, Chiolero R, Schaller MD, Perret C, Spinnler O, Blondel J, Siegrist H. Nosocomial pneumonia in mechanically ventilated patients receiving antacid, ranitidine, or sucralfate as prophylaxis for stress ulcer. A randomized controlled trial. Ann Intern Med. 1994;120:653-662.  [PubMed]  [DOI]
45.  Reusser P, Zimmerli W, Scheidegger D, Marbet GA, Buser M, Gyr K. Role of gastric colonization in nosocomial infections and endotoxemia: a prospective study in neurosurgical patients on mechanical ventilation. J Infect Dis. 1989;160:414-421.  [PubMed]  [DOI]
46.  Ryan P, Dawson J, Teres D, Celoria G, Navab F. Nosocomial pneumonia during stress ulcer prophylaxis with cimetidine and sucralfate. Arch Surg. 1993;128:1353-1357.  [PubMed]  [DOI]
47.  Thomason MH, Payseur ES, Hakenewerth AM, Norton HJ, Mehta B, Reeves TR, Moore-Swartz MW, Robbins PI. Nosocomial pneumonia in ventilated trauma patients during stress ulcer prophylaxis with sucralfate, antacid, and ranitidine. J Trauma. 1996;41:503-508.  [PubMed]  [DOI]
48.  Yildizdas D, Yapicioglu H, Yilmaz HL. Occurrence of ventilator-associated pneumonia in mechanically ventilated pediatric intensive care patients during stress ulcer prophylaxis with sucralfate, ranitidine, and omeprazole. J Crit Care. 2002;17:240-245.  [PubMed]  [DOI]
49.  Nealis TB, Howden CW. Is there a dark side to long-term proton pump inhibitor therapy? Am J Ther. 2008;15:536-542.  [PubMed]  [DOI]
50.  Altman KW, Waltonen JD, Hammer ND, Radosevich JA, Haines GK. Proton pump (H+/K+-ATPase) expression in human laryngeal seromucinous glands. Otolaryngol Head Neck Surg. 2005;133:718-724.  [PubMed]  [DOI]
51.  Altman KW, Waltonen JD, Tarjan G, Radosevich JA, Haines GK. Human lung mucous glands manifest evidence of the H+/K+-ATPase proton pump. Ann Otol Rhinol Laryngol. 2007;116:229-234.  [PubMed]  [DOI]
52.  Aybay C, Imir T, Okur H. The effect of omeprazole on human natural killer cell activity. Gen Pharmacol. 1995;26:1413-1418.  [PubMed]  [DOI]
53.  Capodicasa E, De Bellis F, Pelli MA. Effect of lansoprazole on human leukocyte function. Immunopharmacol Immunotoxicol. 1999;21:357-377.  [PubMed]  [DOI]
54.  Mikawa K, Akamatsu H, Nishina K, Shiga M, Maekawa N, Obara H, Niwa Y. The effects of cimetidine, ranitidine, and famotidine on human neutrophil functions. Anesth Analg. 1999;89:218-224.  [PubMed]  [DOI]
55.  Noble DW. Proton pump inhibitors and stress ulcer prophylaxis: pause for thought? Crit Care Med. 2002;30:1175-1176.  [PubMed]  [DOI]
56.  Scaringi L, Cornacchione P, Fettucciari K, Rosati E, Rossi R, Marconi P, Capodicasa E. Activity inhibition of cytolytic lymphocytes by omeprazole. Scand J Immunol. 1996;44:204-214.  [PubMed]  [DOI]
57.  Yoshida N, Yoshikawa T, Tanaka Y, Fujita N, Kassai K, Naito Y, Kondo M. A new mechanism for anti-inflammatory actions of proton pump inhibitors--inhibitory effects on neutrophil-endothelial cell interactions. Aliment Pharmacol Ther. 2000;14 Suppl 1:74-81.  [PubMed]  [DOI]
58.  Zedtwitz-Liebenstein K, Wenisch C, Patruta S, Parschalk B, Daxböck F, Graninger W. Omeprazole treatment diminishes intra- and extracellular neutrophil reactive oxygen production and bactericidal activity. Crit Care Med. 2002;30:1118-1122.  [PubMed]  [DOI]
59.  Wilder-Smith CH, Merki HS. Tolerance during dosing with H2-receptor antagonists. An overview. Scand J Gastroenterol Suppl. 1992;193:14-19.  [PubMed]  [DOI]
60.  Moride Y, Abenhaim L. Evidence of the depletion of susceptibles effect in non-experimental pharmacoepidemiologic research. J Clin Epidemiol. 1994;47:731-737.  [PubMed]  [DOI]
61.  Chiu HF, Huang YW, Chang CC, Yang CY. Use of proton pump inhibitors increased the risk of hip fracture: a population-based case-control study. Pharmacoepidemiol Drug Saf. 2010;19:1131-1136.  [PubMed]  [DOI]
62.  Corley DA, Kubo A, Zhao W, Quesenberry C. Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at-risk patients. Gastroenterology. 2010;139:93-101.  [PubMed]  [DOI]
63.  Grisso JA, Kelsey JL, O'Brien LA, Miles CG, Sidney S, Maislin G, LaPann K, Moritz D, Peters B. Risk factors for hip fracture in men. Hip Fracture Study Group. Am J Epidemiol. 1997;145:786-793.  [PubMed]  [DOI]
64.  Kaye JA, Jick H. Proton pump inhibitor use and risk of hip fractures in patients without major risk factors. Pharmacotherapy. 2008;28:951-959.  [PubMed]  [DOI]
65.  Targownik LE, Lix LM, Metge CJ, Prior HJ, Leung S, Leslie WD. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ. 2008;179:319-326.  [PubMed]  [DOI]
66.  Vestergaard P, Rejnmark L, Mosekilde L. Proton pump inhibitors, histamine H2 receptor antagonists, and other antacid medications and the risk of fracture. Calcif Tissue Int. 2006;79:76-83.  [PubMed]  [DOI]
67.  Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006;296:2947-2953.  [PubMed]  [DOI]
68.  Colin-Jones DG. The role and limitations of H2-receptor antagonists in the treatment of gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 1995;9 Suppl 1:9-14.  [PubMed]  [DOI]
69.  Olbe L, Cederberg C, Lind T, Olausson M. Effect of omeprazole on gastric acid secretion and plasma gastrin in man. Scand J Gastroenterol Suppl. 1989;166:27-32; discussion 41-2.  [PubMed]  [DOI]
70.  Schuler A. Risks versus benefits of long-term proton pump inhibitor therapy in the elderly. Geriatr Nurs. 2007;28:225-229.  [PubMed]  [DOI]
71.  Lesclous P, Guez D, Baroukh B, Vignery A, Saffar JL. Histamine participates in the early phase of trabecular bone loss in ovariectomized rats. Bone. 2004;34:91-99.  [PubMed]  [DOI]
72.  Lesclous P, Guez D, Saffar JL. Short-term prevention of osteoclastic resorption and osteopenia in ovariectomized rats treated with the H(2) receptor antagonist cimetidine. Bone. 2002;30:131-136.  [PubMed]  [DOI]
73.  Dobigny C, Saffar JL. H1 and H2 histamine receptors modulate osteoclastic resorption by different pathways: evidence obtained by using receptor antagonists in a rat synchronized resorption model. J Cell Physiol. 1997;173:10-18.  [PubMed]  [DOI]
74.  Jacobs NA, Trew DR. Occlusion of the central retinal artery and ocular neovascularisation: an indirect association? Eye (Lond). 1992;6:599-602.  [PubMed]  [DOI]
75.  Adachi Y, Shiota E, Matsumata T, Iso Y, Yoh R, Kitano S. Bone mineral density in patients taking H2-receptor antagonist. Calcif Tissue Int. 1998;62:283-285.  [PubMed]  [DOI]
76.  Mattsson JP, Väänänen K, Wallmark B, Lorentzon P. Omeprazole and bafilomycin, two proton pump inhibitors: differentiation of their effects on gastric, kidney and bone H(+)-translocating ATPases. Biochim Biophys Acta. 1991;1065:261-268.  [PubMed]  [DOI]
77.  Bo-Linn GW, Davis GR, Buddrus DJ, Morawski SG, Santa Ana C, Fordtran JS. An evaluation of the importance of gastric acid secretion in the absorption of dietary calcium. J Clin Invest. 1984;73:640-647.  [PubMed]  [DOI]
78.  Shangraw RF. Factors to consider in the selection of a calcium supplement. Public Health Rep. 1989;104 Suppl:46-50.  [PubMed]  [DOI]
79.  Nordin BE. Calcium and osteoporosis. Nutrition. 1997;13:664-686.  [PubMed]  [DOI]
80.  Wood RJ, Serfaty-Lacrosniere C. Gastric acidity, atrophic gastritis, and calcium absorption. Nutr Rev. 1992;50:33-40.  [PubMed]  [DOI]
81.  Campbell-Thompson M, Reyher KK, Wilkinson LB. Immunolocalization of estrogen receptor alpha and beta in gastric epithelium and enteric neurons. J Endocrinol. 2001;171:65-73.  [PubMed]  [DOI]
82.  Zhang Y, Lai WP, Wu CF, Favus MJ, Leung PC, Wong MS. Ovariectomy worsens secondary hyperparathyroidism in mature rats during low-Ca diet. Am J Physiol Endocrinol Metab. 2007;292:E723-E731.  [PubMed]  [DOI]
83.  Sozzi M, Valentini M, Figura N, De Paoli P, Tedeschi RM, Gloghini A, Serraino D, Poletti M, Carbone A. Atrophic gastritis and intestinal metaplasia in Helicobacter pylori infection: the role of CagA status. Am J Gastroenterol. 1998;93:375-379.  [PubMed]  [DOI]
84.  Matsubara M, Sakata I, Wada R, Yamazaki M, Inoue K, Sakai T. Estrogen modulates ghrelin expression in the female rat stomach. Peptides. 2004;25:289-297.  [PubMed]  [DOI]
85.  Sakata I, Tanaka T, Yamazaki M, Tanizaki T, Zheng Z, Sakai T. Gastric estrogen directly induces ghrelin expression and production in the rat stomach. J Endocrinol. 2006;190:749-757.  [PubMed]  [DOI]
86.  Fukushima N, Hanada R, Teranishi H, Fukue Y, Tachibana T, Ishikawa H, Takeda S, Takeuchi Y, Fukumoto S, Kangawa K. Ghrelin directly regulates bone formation. J Bone Miner Res. 2005;20:790-798.  [PubMed]  [DOI]
87.  Brandt D. Acid suppression and pneumonia. Am J Nurs. 2005;105:21.  [PubMed]  [DOI]
88.  Gullberg B, Johnell O, Kanis JA. World-wide projections for hip fracture. Osteoporos Int. 1997;7:407-413.  [PubMed]  [DOI]
89.  Kanis JA. The incidence of hip fracture in Europe. Osteoporos Int. 1993;3 Suppl 1:10-15.  [PubMed]  [DOI]
90.  O'Connell MB, Madden DM, Murray AM, Heaney RP, Kerzner LJ. Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial. Am J Med. 2005;118:778-781.  [PubMed]  [DOI]