Proton Pump Inhibitor (PPI) Therapy and Bone Fractures

In 2008, a number of media reports focused on a study from the Canadian Medical Association Journal (CMAJ), suggesting an association between consuming proton pump inhibitors, a potent class of gastric acid suppressing drugs, and an increased risk of osteoporosis-related fractures, including hip fractures.1 To understand the results of this new research beyond the media headlines, a thorough appreciation of the background and some of the details of this matter are essential.


A number of medications help reduce the amount of acid in the stomach; either by neutralizing the acid (lowering the pH) with antacids, for example, or by suppressing the production or secretion of gastric acid, as are the mechanisms of histamine-two receptor antagonists (H2RAs) and proton pump inhibitors (PPIs).

Since their introductions, H2RAs and PPIs have become widely prescribed for acid-related disorders, including gastroesophageal reflux disease (GERD), peptic ulcer disease, and for healing esophageal ulcers. Compared to antacids or H2RAs, PPIs are more reliable and effective at reducing gastric acidity2 and promoting healing of peptic ulcers and ulcerative esophagitis, due to refluxing acid. PPIs are also an important component of the medical regimens used to eradicate Helicobacter pylori, an infectious organism associated with peptic ulcers.3,4

Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture,5 affecting approximately 1 in 4 women and 1 in 8 men in Canada.6 Vertebral (spine) and hip fractures are associated with increased mortality; about 20% in those who suffer a hip fracture die within one year and the remainder are institutionalized or have some level of altered function.5 Tools for assessing the 10-year risk of fracture are available to help identify those at greater risk.7,8

Recent publications

The study noted above, published in the August 12, 2008 issue of the CMAJ, details research by Targownik et al. using a Manitoba health claims database comparing a group of patients who had received PPIs to a group who had not received PPIs.1 Researchers matched 15,792 cases of osteoporosis-related fractures (in the spine, hip, or wrist) with 47,289 controls and conducted analyses to determine if there is an association between fractures and PPI therapy. The study reported no significant association between the overall risk of an osteoporotic fracture and the use of PPIs for durations of six years or fewer. However, usage of PPI therapy for seven or more years was associated with increased risk of an osteoporosis-related fracture. In addition, an increased risk of hip fracture was associated with five or more years of PPI therapy and an even greater risk of hip fracture was associated with PPI therapy for seven or more years. PPI therapy and fracture may not have a cause and effect relationship but this study is considered as ‘hypothesis generating’, which means that it should only be used as a guide to conduct further investigations. There are inherent weaknesses in these types of retrospective analyses, and only a randomized controlled trial can prove or refute any true cause and effect.

A 2006 study, using a different administrative database, reported similar results. Yang et al., published in the Journal of the American Medical Association, used the General Practice Research Database from the United Kingdom to examine any association between PPI therapy and risk of hip fracture.9 In this analysis, increased hip fracture risk was associated with more than one year of PPI therapy and a greater risk of hip fracture with longer term and high dose PPI therapy. This study found an associated increase in hip fractures among those receiving H2RA therapy, compared to those who were not receiving this therapy.

A study by Vestergaard et al., also in 2006, analyzed data from a Danish population health database and compared patients who have ever consumed PPIs, H2RAs, and/or antacids with those patients who have never consumed any of these types of drugs.10 The authors report that the use of PPIs is associated with an increase in overall fracture risk (any fracture site) as well as hip fracture risk, for individuals on PPI therapy within the last year. Surprisingly, H2RA therapy was associated with a decrease in fracture risk (any site) as well as a decrease in hip fracture rate if patients had used H2RA within the last year. This would imply that H2RAs might prevent fractures in patients who take them, contradicting other studies.

H2RAs include cimetidine, ranitidine (Zantac®), famotidine (Pepcid®), and nizatidine (Axid®). PPIs include omeprazole (Losec®), lansoprazole (Prevacid®), pantoprazole (Pantoloc®), esomeprazole (Nexium®), and rabeprazole (Pariet™).

All medications, while helpful for their clinical or positive medicinal effect, have the potential for an adverse effect on the body. The goal of drug therapy is to use medications in ways that maximize their benefits and preferably avoid, or at least minimize, their side effects. We do this by using all of the available studies and scientific evidence to guide our decisions, putting more weight on higher level, definitive, or reliable studies. The gold standard medically accepted method for testing drug outcomes and side effects are Randomized Controlled Trials (RCT).

It is important to note that there are no definitive RCTs demonstrating the increased risk of fracture with PPIs, H2RAs, or antacids, nor definitive RCTs reporting decreased risk of fractures with H2RAs. Misleading results from database studies, sometimes called epidemiological studies, could occur from inaccurate study assumptions or omissions of data that could lead to different results. There are many other reasons why inaccuracies could occur in epidemiological studies and, therefore, information acquired from these kinds of studies requires definitive confirmation.

A position statement issued by the Canadian Association of Gastroenterology states, “Current data would not support particular care in prescribing PPI therapy due to concern about risk of hip fracture. There is no persuasive evidence that the association is causal although this can never be excluded as a possibility”.11 The evidence is not definitive on whether PPIs cause fractures, and further studies are necessary to clarify the true risk, if any.

What to do if you are taking PPIs

Your physician can help you assess the ongoing benefits and risks of continued PPI therapy for you as an individual. Proton pump inhibitors improve quality of life and reduce symptoms of acid-related conditions and therefore, patients, as advised by their physicians, could remain on PPIs when expected benefits outweigh the risks. Any association between consuming PPIs and fractures remains unsubstantiated. However, some evidence indicates that acid suppression may reduce calcium absorption and thereby lead to an increase in the risk of fracture, though this is controversial.1,10,11,12 Calcium is an important factor in maintaining strong bones and preventing fractures, thus, be sure to discuss calcium intake with your healthcare provider.

Considering the studies discussed above, and other data, PPI therapy beyond one year should be re-evaluated, focusing on the benefits of continuation weighed against the potential risks. The above data are not definitive and should not solely drive the decision to discontinue therapy; however, as with any medication, it is prudent to use the lowest dose effective for the treatment, for the shortest duration possible. Physicians may recommend intermittent use of PPIs in some situations. In addition, when taking a calcium supplement, it is sensible to consider taking it with food, which increases gastric acidity naturally, and this could aid in calcium absorption.

Alan Low, BSc.(Pharm.), Pharm. D., RPh, ACPR, FCSHP, CCD
Clinical Associate Professor, Faculty of Pharmaceutical Sciences, UBC
First published in the Inside Tract® newsletter issue 168 – July/September 2008
1. Targownik LE, et al. Use of proton pump inhibitors and risk of osteoporosis-related fractures. Canadian Medical Association Journal. 2008;179:319-26.
2. Boparai V, et al. Guide to the use of proton pump inhibitors in adult patients. Drugs. 2008;68(7):925-947.
3. Chiba N, et al. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: A meta-analysis. Gastroenterology. 1997;112:1798-810.
4. Ford A, et al. Eradication therapy for peptic ulcer disease in Helicobacter pylori positive patients. Cochrane Database of Systematic Reviews. 2004;4:CD003840.
5. National Institutes of Health Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. Journal of the American Medical Association. 2001;285(6):785-95. 6. Brown JP, et al. Clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. Canadian Medical Association Journal. 2002;167:S1-S36.
7. Siminoski K, et al. Recommendations for bone mineral density reporting in Canada. Canadian Association of Radiologists Journal. 2005;Jun;56(3):178-88.
8. FRAX – WHO Fracture risk assessment tool. World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK. Available at: Accessed September 20, 2008.
9. Yang YX, et al. Long-term proton pump inhibitor therapy and risk of hip fracture. Journal of the American Medical Association. 2006;296:2947-2953.
10. Vestergaard P, et al. Proton pump inhibitors, histamine H2 receptor antagonists, and other antacid medications and the risk of fracture. Calcified Tissue International. 2006;79:76-83.
11. Canadian Association of Gastroenterology. Position Statement: Hip fracture and proton pump inhibitor therapy. Canadian Association of Gastroenterology, August 15, 2008. Available at: Accessed Sept 20, 2008.
12. Wright MJ, et al. Proton pump-inhibiting drugs, calcium homeostasis, and bone health. Nutrition Reviews. 2008;66:103-8.