The clinical tolerability profile of alendronate

Alendronate is a potent bisphosphonate that is effective in preventing osteoporotic fractures. Clinical trial data involving over 17,000 women provide a large, placebo-controlled experience from which alendronate has been demonstrated to be safe and well tolerated. We review the safety profile of alendronate in the context of its pharmacology, preclinical information and published literature on bisphosphonates. The clinical data include information from 1) the two primary Phase III osteoporosis treatment studies involving 994 women with postmenopausal osteoporosis treated with alendronate for up to 3 years; 2) upper gastrointestinal (GI) tolerability data (including special subgroup analyses) from the Fracture Intervention Trial (FIT), involving 2027 women with prior vertebral fractures; 3) an endoscopy study, and 4) postmarketing experience. Because all bisphosphonates have the potential to irritate the upper GI mucosa, we specifically investigated the safety and tolerability profile with respect to the upper GI tract. In the Phase III trials, alendronate 5 or 10 mg/day was well tolerated, with no increase relative to placebo in the incidence of overall adverse experiences (ie, inclusive of all events, not just those related to the GI tract). In the Phase III trials, alendronate 5 mg/day or 10 mg/day was well tolerated, with no increase relative to placebo in the incidence of overall adverse experiences. The incidence of upper gastrointestinal adverse experiences, overall, was similar among alendronate 5 mg or 10 mg and placebo, with abdominal pain and dysphagia being the only individual adverse experiences that were significantly increased (with alendronate 10 mg). Esophageal adverse experiences were uncommon, being reported in 8 (2.0%) patients receiving placebo and 9 (4.6%) patients taking alendronate 10 mg. None of the events occuring on alendronate therapy were serious or resulted in discontinuation. Tolerability was not affected by a wide range of concomitant medications including nonsteroidal anti-inflammatory drugs. Additional analyses of the 2027 postmenopausal women with vertebral fractures enrolled in FIT demonstrated that alendronate use was not associated with a significant increase in upper GI events, esophageal events, or gastroduodenal adverse events, even among women at high risk for upper GI complications (those older than 75 yr, those with previous upper GI disease, or those using NSAIDs). Esophageal adverse experiences (including esophagitis and esophageal ulcers) have been reported with alendronate in postmarketed use. A high proportion of these reports involved patients who did not follow the dosing instructions and probably relate to the irritant potential of refluxed gastric acid containing alendronate. Consistent with the antiresorptive mechanism of action of alendronate, asymptomatic decreases in serum calcium and phosphate were observed with alendronate treatment in the clinical trials. There were no other laboratory changes noted with alendronate. Now marketed in 78 countries and used by over 3 million women, the safety profile of alendronate, when dosed appropriately, has been consistent with that of the clinical trial experience. In view of the increased morbidity and mortality associated with fractures, and the proven efficacy of alendronate to reduce fracture risk, the benefit/risk ratio of alendronate remains highly favourable.