How Common are Upper Gastrointestinal (GI) Adverse Effects in Use of Alendronate and Risedronate?

Bisphosphonate-induced upper GI adverse events are commonly cited, but the risk may be overstated and more associated with inappropriate administration. The probable mechanism for such effects is local irritation.

Another possibility is that people with osteoporosis have a high incidence of upper GI complaints even without taking bisphosphonates. Indeed, in clinical trials, similar numbers of patients receiving placebo reported upper GI adverse effects as did patients receiving active drug.

Miller et al(11) addressed this issue in a placebo-controlled trial of alendronate rechallenge in 172 postmenopausal women with osteoporosis, all of whom had stopped taking alendronate because of adverse upper GI events that occurred while taking the drug. After 8 weeks of rechallenge therapy, 14.5% of patients receiving alendronate and 17.3% of patients receiving placebo had stopped treatment because of upper GI complaints, including abdominal pain (29.6%), acid regurgitation (25.9%), nausea (18.5%), and gastroesophageal reflux (11.1%). The investigators suggested that upper GI complaints reported during alendronate therapy reflected a high background incidence of upper GI complaints rather than an adverse effect of alendronate.(11)

In another study, conducted by Adachi et al,(12) 66 postmenopausal women who had previously stopped taking alendronate because of upper GI adverse effects received either risedronate 5 mg daily or placebo. After 3 months, 16.1% of patients had stopped taking placebo, compared with 11.4% of patients receiving risedronate. The investigators concluded that risedronate is as well tolerated as placebo in patients who cannot tolerate alendronate.

Are there any differences in GI adverse effects?

Lanza et al(13) assessed the effects of alendronate and risedronate on the incidence of gastric ulcers and on the esophageal and gastroduodenal mucosa in 515 postmenopausal women age 40 and older. Patients received either risedronate 5 mg/day or alendronate 10 mg/day for 14 days, while abstaining from alcohol, smoking, and nonsteroidal anti-inflammatory drugs.

Gastric ulcer, defined as a break of at least 3-mm in the gastroduodenal mucosa extending through the muscularis mucosa, was observed endoscopically in 4.1% of the risedronate group vs 13.2% of the alendronate group (P <.001). The investigators concluded that at doses used for osteoporosis treatment, risedronate was associated with a significantly lower incidence of gastric ulcers than alendronate.

However, this study had several drawbacks: it was a short-term study in healthy postmenopausal women and did not include a placebo group to determine the expected risks of gastric ulceration without intervention. The clinical relevance of the small asymptomatic ulceration observed remains unclear.(14)

Higher doses tested. Lanza et al(15) also assessed the potential of alendronate and risedronate to cause endoscopically observed upper GI mucosal irritation, using the highest approved doses (ie, those used in the treatment of Paget disease) and a scale for scoring mucosal erosions.

After a 28-day trial of alendronate 40 mg a day, risedronate 30 mg a day, placebo, or placebo with aspirin 650 mg four times a day for the last 7 days, patients taking risedronate and alendronate had comparable gastric and duodenal erosion scores, and these scores were significantly lower than those in patients taking aspirin.15 Esophageal erosion scores were comparable in all groups.

However, gastric ulcers (defined as larger, deeper endoscopic erosions) occurred in 3% of patients taking risedronate or alendronate, in 60% of patients taking aspirin, and in none of the patients in the placebo group. Adverse GI effects were reported by 12% in the alendronate group, 15% in the risedronate group, 35% in the aspirin group, and 22% in the placebo group.

The investigators concluded that alendronate and risedronate are generally well tolerated and that they pose a very low risk for clinically important gastric irritation, even at the highest dosages used.

Minimal Drug Interactions

Neither risedronate nor alendronate induces or inhibits the cytochrome P450 enzyme system, so interaction with other drugs is minimal. However, clinicians should note the following:

—Co-administration of calcium supplements, antacids, or oral medications with divalent cations interfere with absorption of risedronate and alendronate

—The concomitant use of aspirin and highdose alendronate should be avoided because of an increased incidence of upper GI adverse events in clinical trials.

Peters ML, Leonard M, Licata AA. Role of Alendronate and Risedronate in Preventing and Treating Osteoporosis. Cleve Clin J Med 2001;68:945-951.