Proton Pump Inhibitors: Review of Benefits and Fracture Risk

Use of medication at the lowest dosage, for the shortest duration likely to achieve the desired outcome, is one of the guiding principles of pharmacotherapy. In addition, whenever possible, selection of a medication regimen for a patient's chronic health condition or acute illness is based on evidence obtained from randomized controlled trials (RCTs). In the absence of definitive RCT data, practice decisions are guided by clinical experience and judgment. All these elements are integrated to formulate an appropriate medication regimen for each patient, which is then modified as needed based on assessments over time.

With regard to medication related adverse effects, NPs not only monitor patients for those that are anticipated, but they also keep abreast of postmarketing surveillance reports. This approach enables NPs to observe trends in certain patient populations or recognize an adverse effect in an individual patient or in patients who may be at risk. With these principles and concepts as a foundation, this column offers a brief discussion of proton pump inhibitors (PPIs), specifically with regard to these agents' major benefit (potent acid suppression) and a serious risk posed by long-term use (fracture).

Available proton pump inhibitors, which are listed in Table 1(see sidebar), are extremely potent inhibitors of gastric acid, producing a profound, long-lasting antisecretory effect.¹ This effect can maintain gastric pH>4, even during a postprandial acid surge.^1,2 PPIs are more effective than histamine-2 receptor antagonists (H2RAs; eg, cimetidine, famotidine, nizatidine, ranitidine) for commonly occurring and more serious gastric acid-associated disorders (Table 2).

All PPIs degrade in an acidic environment, so they are most commonly formulated in delayed release capsules or tablets. To maximize efficacy, patients are typically instructed to take PPIs in the morning, 15-30 minutes before breakfast. If nocturnal symptoms are present, patients may benefit from PPI administration prior to the evening meal; if twice-daily dosing is required, the night-time dose is administered prior to a meal or snack about 10-12 hours after the morning dose.³ Recommended dosages for PPIs in seniors, with regard to specific indications for use, are found in reference 4.⁴

Although usually well tolerated, PPIs can have adverse effects such as headache, dizziness, nausea, and constipation, and they can lead to vitamin B12 deficiency.¹ In addition, several observational studies have demonstrated an association between long-term use of PPIs and fracture of the hip^5,6 or vertebrae.⁶ Other studies have shown inconsistent findings with regard to the link between the use of acid-suppressive drugs such as PPIs and H2RAs and fracture risk.^7,8 In patients with an increased risk for fracture, achlorhydria (absence of gastric acid secretion) is thought to lead to malabsorption and deficiencies of calcium and vitamin B12, ultimately resulting in bone loss.^7,8

In the May-June 2011 issue of Annals of Family Medicine, Eom et al⁹ reported the results of a metaanalysis of the association between PPIs and fracture risk. (A metaanalysis, also known as a quantitative systematic review, combines and statistically evaluates data from previously conducted studies; conclusions are drawn from a summarization of the results.) These investigators analyzed 11 studies—a variety of case–control, nested case–control, and cohort studies—and found possible evidence linking use of PPIs, although not H2RAs, to an increased fracture risk.9 PPIs were associated with a 29% increased risk for fracture, including fractures of the hip (31% increased risk) and fractures of the vertebrae (54% increased risk).

There was no difference in the results for PPIs and H2RAs with regard to gender.9 In addition, the dose of PPI or H2RA did not significantly affect the associated risks for fracture. However, higher risk for any fracture and for hip fracture was associated with long-term use of PPIs.9 In an editorial accompanying the meta-analysis, Gill et al7 asserted that the findings regarding increased PPI-associated fracture risk were robust and consistent across study design and across therapy type: high-dose, usual-dose, long-term (>1-year), and any use. Because PPIs are one of the most widely used class of pharmacologic agents in the United States, the potentially increased risk for fracture associated with their use is of great relevance both for individual patients and for the healthcare system as a whole. Eon et al9 recommended that clinicians carefully consider their decision to prescribe PPIs for patients who are at increased risk for fracture secondary to age or other factors.

Preventing Falls—Most osteoporotic fractures are precipitated by falls.¹⁰ Persons particularly predisposed to falls are those who take medications that impair mental alertness, those who are old or frail, and those who have had a stroke.¹⁰ According to leading experts, an effective approach to osteoporosis treatment must include a program for fall prevention.¹⁰ This program includes teaching patients strategies to reduce the risk of falling in the home—for example, minimizing clutter, anchoring rugs, lighting hallways and stairwells, and installing handrails in bathrooms. For information about additional measures and the use of hip protectors, refer to online reference 10.¹⁰ Calcium supplementation is considered as a potential means to counteract the harmful effect of PPIs on bone density;⁷ vitamin D supplementation may also be necessary.

Pharmacotherapy—Various drug classes and individual drugs have been approved by the FDA for the prevention and/or treatment of osteoporosis; these agents may be appropriate for PPI users at risk for osteoporotic fracture based on a risk–benefit ratio. Online reference 10 provides a comprehensive table of the bisphosphonates (eg, alendronate, risendronate, ibandronate) and other agents (eg, estrogen, calcitonin, denosumab, raloxifene, zoledronic acid, teriparatide) used in this regard.¹⁰ This reference provides medication dosages for postmenopausal osteoporosis and for glucocorticoid-induced osteoporosis.

With regard to specific recommendations for PPI use in the spectrum of patients seen in primary care, NPs are directed to online reference 7.⁷ The authors underscore the importance of balancing risks and benefits of PPIs, as with any treatment. These general recommendations are made to PPI prescribers: ^7-9,11-14

Exercise minimal concern regarding PPI risks when treating an acute condition that may be lifethreatening (eg, gastric or duodenal ulcer) or when aiming to prevent a serious condition (eg, gastrointestinal [GI] complications) in long-term NSAID users.

Prescribe on-demand PPI therapy for patients with uncomplicated GERD in whom no evidence of erosive esophagitis or Barrett’s esophagus exists; once daily PPI maintenance therapy is advised for patients with erosive esophagitis or Barrett’s esophagus.

Prescribe a 4- to 6-week course of empiric PPI therapy for predominant GERD without evidence of Helicobacter pylori infection and for nonspecific dyspepsia without alarm symptoms (eg, dysphagia, odynophagia, GI bleeding or anemia, weight loss, chest pain). Discontinue PPI therapy or step down to a lower-potency regimen thereafter. 

For atypical symptoms of GERD (eg, chronic hoarseness), consider a trial of PPI therapy. 

Consider co-therapy with PPIs for GI protection in NSAID users with a history of peptic ulcer disease; in patients receiving warfarin, aspirin, or glucocorticoids; and in the elderly.

Several studies suggest that the frequency of GERD complications (eg, erosive esophagitis, Barrett’s esophagitis) is significantly higher in seniors; PPIs are considered first-line treatment for GERD and erosive esophagitis in this patient population.¹⁵

Some studies have shown an increased risk for Clostridium difficile colitis and other enteric infections associated with PPI use.⁹ Less agreement exists regarding an increased risk for ambulatory pneumonia associated with PPI use.⁸ PPI-associated hypomagnesemia (an alerting caution in patients receiving digoxin concurrently) has been formally addressed as a warning by the FDA, although controlled studies are not available to elucidate this finding.¹⁶

NPs need to be aware of the findings of a recent meta-analysis showing that use of PPIs, but not H²RAs, is associated with an increased risk for fracture. Based on past and current evidence, familiarization with the recommendations for PPI use is advised so that regimens can be individually tailored based on a benefit–risk ratio.