Use of proton pump inhibitors and risk of osteoporosis-related fractures

Laura E. Targownik; Lisa M. Lix; Colleen J. Metge; Heather J. Prior; Stella Leung; William D. Leslie

doi:10.1503/cmaj.071330

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Smoking and alcohol, low BMI: which role in the pathway?
Mathieu Forster

Posted on: 17 December 2008
PPIs, B12, and falls
Henry Olders

Posted on: 18 November 2008
The problems with acid suppression
Richard Nahas

Posted on: 21 August 2008
Omeprazole and Vitamin B 12 Absorption
Preston J Chandler

Posted on: 18 August 2008

Posted on: (17 December 2008)
Page navigation anchor for Smoking and alcohol, low BMI: which role in the pathway?
Smoking and alcohol, low BMI: which role in the pathway?
Mathieu Forster
In this very important and interesting research, the authors state that PPIs effect on osteoporosis-related fractures might be "similar in size to those for other established osteoporotic-fracture risk factors, such as smoking, low body mass index and excessive alcohol intake".
However, none of these factors have been taken into account in the analysis. Were both groups comparable in term of these three variables...
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In this very important and interesting research, the authors state that PPIs effect on osteoporosis-related fractures might be "similar in size to those for other established osteoporotic-fracture risk factors, such as smoking, low body mass index and excessive alcohol intake".
However, none of these factors have been taken into account in the analysis. Were both groups comparable in term of these three variables? If not, what is their role in the observed associations? For instance, PPIs users might be less likely to be active smokers because of gastroesophageal reflux disease but could at the same time have a higher prevalence of smoking history. This may have an impact on associations measures, with an unknown magnitude.
This study relies on administrative data analysis, whose main aim was probably far from osteoporosis etiologic research interests. This does not mean that such data are inadequate for health research , but that we should be more critical about the inference drawn.
Conflict of Interest:
None declared
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Competing Interests: None declared.
Posted on: (18 November 2008)
Page navigation anchor for PPIs, B12, and falls
PPIs, B12, and falls
Henry Olders
While the authors of this important paper(1) mention the importance of falls as a risk factor for fracture, neither they nor the authors of the accompanying editorial(2) address the possibility, raised in a previous comment by Preston J. Chandler, that proton pump inhibitors (PPIs) may increase fracture risk by contributing to vitamin B12 deficiency which then increases the risk of falling. I would like to expand o...
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While the authors of this important paper(1) mention the importance of falls as a risk factor for fracture, neither they nor the authors of the accompanying editorial(2) address the possibility, raised in a previous comment by Preston J. Chandler, that proton pump inhibitors (PPIs) may increase fracture risk by contributing to vitamin B12 deficiency which then increases the risk of falling. I would like to expand on this hypothesis.
It is well-known that gastric acid is required to cleave food-bound vitamin B12 from food so it can subsequently be absorbed. Conditions which interfere with gastric acid production, most commonly atrophic gastritis but also treatment with PPIs, may thus impair absorption of food-bound B12(3). According to the Institute of Medicine of the National Academy of Sciences in the United States, "10 to 30 percent of older people may be unable to absorb naturally occurring vitamin B12" [http://books.nap.edu/openbook.php? record_id=6015&page=306, accessed 08-11-12].
There are a number of mechanisms through which a PPI-induced B12 deficiency might increase the risk of falling: dizziness and vertigo from anemia; decreases in position sense and muscle weakness, both affecting most commonly the lower extremities; cognitive impairment that may lead to poor judgment about utilizing walkers or canes, or making safe transfers between beds, wheelchairs, and so on. Finally, low B12 may cause orthostatic hypotension(4).
Besides increasing risk of falling, vitamin B12 deficiency may also impair bone formation and lead to decreased bone mineral density(5) which may affect fracture risk also.
The above-mentioned Institute of Medicine, with the active involvement of Health Canada [http://books.nap.edu/openbook.php? isbn=0309065542&page=1, accessed 08-11-12], recommended in 1998 that every adult over the age of 50 get most of their B12 from synthetic sources. They stated, "... it is advisable for those older than 50 years to meet their RDA mainly by consuming foods fortified with vitamin B12 or a vitamin B12-containing supplement" [http://books.nap.edu/openbook.php? record_id=6015&page=306, accessed 08-11-12]. While in the U.S. many commonly available foods such as breakfast cereal are B12-fortified, this is not the situation in Canada, which means that vitamin supplements are necessary. Unfortunately, even following the recommendation may be insufficient to prevent decline in B12 levels for patients taking PPIs(6) and higher doses may be necessary.
In summary, while PPI use may increase risk of fracture through calcium malabsorption, another important and easily modifiable factor may be PPI- induced impairment of food-bound vitamin B12 absorption.
References
1. 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.
2. Richards JB, Goltzman D. Proton pump inhibitors: balancing the benefits and potential fracture risks. CMAJ. 2008;179:306-307.
3. Valuck RJ, Ruscin JM. A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of vitamin B12 deficiency in older adults. J Clin Epidemiol. 2004;57:422-428.
4. Moore A, Ryan J, Watts M, Pillay I, Clinch D, Lyons D. Orthostatic tolerance in older patients with vitamin B12 deficiency before and after vitamin B12 replacement. Clin Auton Res. 2004;14:67-71.
5. Tucker KL, Hannan MT, Qiao N et al. Low plasma vitamin B12 is associated with lower BMD: the Framingham Osteoporosis Study. J Bone Miner Res. 2005;20:152-158.
6. Dharmarajan TS, Kanagala MR, Murakonda P, Lebelt AS, Norkus EP. Do acid-lowering agents affect vitamin B12 status in older adults? J Am Med Dir Assoc. 2008;9:162-167.
Conflict of Interest:
None declared
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Competing Interests: None declared.
Posted on: (21 August 2008)
Page navigation anchor for The problems with acid suppression
The problems with acid suppression
Richard Nahas
Proton pump inhibitors (PPIs) promote ulcer healing and treat the symptoms of gastro-esophageal reflux disease (GERD) and other functional disorders by suppressing gastric acid production. However, it has been suggested that PPIs are over-prescribed(1), and that they may increase the risk of pneumonia(2) and gastroenteritis(3) in adults and in children(4), Clostridium difficile-associated diseases(5), and vitamin B12 de...
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Proton pump inhibitors (PPIs) promote ulcer healing and treat the symptoms of gastro-esophageal reflux disease (GERD) and other functional disorders by suppressing gastric acid production. However, it has been suggested that PPIs are over-prescribed(1), and that they may increase the risk of pneumonia(2) and gastroenteritis(3) in adults and in children(4), Clostridium difficile-associated diseases(5), and vitamin B12 deficiency(6). Targownik et al's findings(7) are consistent with existing research linking PPI use with osteoporosis and hip fracture(8).
One glaring omission from this controversy is the irrational notion that suppressing such a critical physiologic function as gastric acid production is acceptable medical therapy. While it is reasonable to temporarily suppress acid production to promote ulcer healing, doing so for decades to eliminate symptoms in functional disorders such as GERD and non-ulcer dyspepsia seems more and more like bad medicine.
GERD is characterized by transient relaxation of the lower esophageal sphincter(9), a disturbance that is completely unrelated to the production of stomach acid. This physiologic disturbance is inappropriately labeled a diagnosis despite the fact that its etiology is unknown. Treating GERD with PPIs can be compared to fixing a leaky faucet in a house by cutting off its water supply. Clearly, what is needed is a better understanding of why and how LES relaxation occurs.
Acid suppression is an important therapeutic strategy in some cases, but the risk associated with long-term PPI use should remind us that there is still much to learn about digestive physiology. It will also hopefully temper the busy clinician's urge to marry symptoms with prescriptions.
1. Naunton M, Peterson GM, Bleasel MD. Overuse of proton pump inhibitors. J Clin Pharm Ther 2000;25:333-340.
2. Laheij RJF, Sturkenboom MCJM, Hassing RJ, Dieleman J, Stricker BHC et al. Risk of community-acquired pneumonia and use of gastric acid- suppressive drugs. JAMA 2004;292:1955-60.
3. Lain L, Ahnen D, McClain C, Solcia E, Walsh JH. Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 2000;14:651-668.
4. Canani RB, Cirillo P, Roggero P, Roman C, Malamisura et al. Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children. Pediatrics 2006;117:817-820.
5. Dial S, Delaney JAC, Schneider V, Suissa S. Proton pump inhibitor use and risk of community-acquired Clostridium difficil-associated disease defined by prescription for oral vancomycin therapy. Can Med Assoc J. 2006;175:745-8.
6. Howden CW. Vitamin B12 levels during prolonged treatment with proton pump inhibitors. J Clin Gastroenterol 2000;30:29-33.
7. Targownik LE, Lix LM, Metge CJ, Prior HJ, Leung S et al. Use of proton pump inhibitors and risk of osteoporosis-related fractures. Can Med Assoc J 2008;179:319-26.
8. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 2006;296:2947-53.
9. Richter JE. Gastroesophageal reflux disease and its complications. In: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed. Saunders Elsevier, 2006.
Conflict of Interest:
None declared
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Competing Interests: None declared.
Posted on: (18 August 2008)
Page navigation anchor for Omeprazole and Vitamin B 12 Absorption
Omeprazole and Vitamin B 12 Absorption
Preston J Chandler
Sirs, Macuard(Ann Intern Med 1994)showed omeprazole causes a dose dependent malabsorption of vitamin B 12. It takes five or so years for clinical combined system disease to appear after absence of B 12. This disorder is associated with a positive Rhomberg's test, hence an increase in falls. A decrease in B 12 may be detected by changes in the blood indices over time. The answer to the increased fracture problem might b...
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Sirs, Macuard(Ann Intern Med 1994)showed omeprazole causes a dose dependent malabsorption of vitamin B 12. It takes five or so years for clinical combined system disease to appear after absence of B 12. This disorder is associated with a positive Rhomberg's test, hence an increase in falls. A decrease in B 12 may be detected by changes in the blood indices over time. The answer to the increased fracture problem might be the co- administration of oral B 12 when long-term proton pump inhibitors are used. These readily available vitamins contain many times the MDR for B12. Large amounts of the vitamin will facilitate intestinal absorption, even in the absence of intrinsic factor.
Conflict of Interest:
None declared
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Competing Interests: None declared.

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