| Sumario: | Background: Fosamax (alendronate sodium, Merck & Co., Inc., Whitehouse Station, NJ, USA) is an effective oral bisphosphonate widely used to treat and prevent osteoporosis, with a safety and tolerability profile similar to placebo in clinical trials. It has been evaluated in clinical trials with over 20,000 participants and up to 10 years duration. Oral bisphosphonates have been associated with esophagitis, which involves events (hat occur prior to absorption and depends on factors such as the frequency of administration, dose, and formulation. Data on non-Fosamax alendronate (NFA) preparations, which contain a form of alendronate with differing excipients, are typically derived from small, single-dose, bioavailability studies. While these studies provide information on systemic effects, they do not address the risk of local esophageal irritation and may, therefore, inadequately characterize safety profiles. Objective: To compare the esophageal irritation potential of NFA preparations to that of the innovator medication. Fosamax. Methods: Two preclinical models of irritation were used. In the first, 24 rabbits were randomized to a single, subcutaneous injection of saline. 10.6 mg of Fosamax in saline, or 10.6 mg NFA in saline. Blinded measurements of skin thickness (a measure of inflammation), wet weight, and histopathology of injection site tissues were performed. In the second study, 16 dogs were anesthetized and a placebo tablet, a 10-mg Fosamax tablet, or a 10-mg NFA tablet was placed by endoscopy in the caudal third of the esophagus for I hour, followed by a saline rinse, daily for 5 days. After the final dose, the dogs were sacrificed and esophageal morphology was examined. Results: In the rabbit injection study, the NFA suspension elicited a significantly greater irritant response than an equivalent suspension of Fosamax. The mean wet weight increase at injection site tissues was 70% greater (P < 0.01) for NFA than Fosamax. Fosamax treatment induced smaller, predominantly foreign-body granuloma type lesions, while NFA induced larger, encapsulated cystic lesions containing the injected material, consistent with a post-inflammatory process. In the esophagus study, all 4 dogs (100%) treated with NFA for 5 days exhibited marked ulcerative esophagitis, whereas only 1 of the 5 dogs treated with Fosamax (20%) had marked ulceration: the remaining 4 dogs had more moderate esophageal changes than those observed in dogs treated with NFA. Conclusions: Generic drugs are expected to have similar efficacy and safety to innovator drugs; however, the greater irritant responses of NFA in rabbits and dogs suggest that important differences may exist between the effects of Fosamax and NFA preparations in the clinical setting. These findings, along with other data demonstrating differences in the disintegration/dissolution profiles of NFA preparations relative to Fosamax, suggest that bioavailability studies may not be adequate for meaningful assessment of the safety and efficacy of NFA or other bisphosphonate preparations.
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