The clinical tolerability profile of alendronate

Alendronate is a potent bisphosphonate that is effective in preventing oste oporotic fractures. Clinical trial data involving over 17,000 women provide a large, placebo-controlled experience from which alendronate has been dem onstrated to be safe and well tolerated. We review the safety profile of al endronate in the context of its pharmacology, preclinical information and p ublished literature on bisphosphonates. The clinical data include informati on from 1) the two primary Phase III osteoporosis treatment studies involvi ng 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) invol ving 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 an d 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 re lative to placebo in the incidence of overall adverse experiences tie, incl usive of all events, not just those related to the Gi tract). In the Phase ill trials alendronate 5 mg/day or 10 mg/day was well tolerated with no inc rease relative to placebo in the incidence of overall adverse experiences. The incidence of upper gastrointestinal adverse experiences, overall, was s imilar among alendronate 5 mg or to mg and placebo, with abdominal pain and dysphagia being the only individual adverse experiences that were signific antly increased (with alendronate 10 mg). Esophageal adverse experiences we re uncommon, being reported in 8 (2.0%) patients receiving placebo and 9 (4 .6%) patients taking alendronate 10 mg. None of the events occurring on ale ndronate therapy were serious or resulted in discontinuation. Tolerability was not affected by a wide range of concomitant medications including nonst eroidal anti-inflammatory drugs. Additional analyses of the 2027 postmenopa usal women with vertebral fractures enrolled in NT demonstrated that alendr onate use was not associated with a significant increase in upper Gi events esophageal events or gastroduodenal adverse events, even among women at hi gh risk for upper GI complications (those older than 75 yr, those with prev ious upper Gi disease, or those using NSAIDs). Esophageal adverse experienc es (including esophagitis and esophageal ulcers) have been reported with al endronate 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. Con sistent with the antiresorptive mechanism of action of alendronate, asympto matic decreases in serum calcium and phosphate were observed with alendrona te treatment in the clinical trials. There were no other laboratory changes noted with alendronate. Now marketed in 78 countries and used by over 3 mi llion women, the safety profile of alendronate, when dosed appropriately: h as been consistent with that of the clinical trial experience. In view of t he increased morbidity and mortality associated with fractures, and the pro ven efficacy of alendronate to reduce fracture risk, the benefit/risk ratio of alendronate remains highly favourable.