Oral Alendronate has been shown to be generally safe and efficacious in the treatment of osteoporosis in postmenopausal women, and is currently marketed in the United States and several other countries for the prevention and treatment of osteoporosis. Alendronate (10 mg daily for 3 years) has been shown to increase bone mineral density relative to placebo treatment by approximately 9% at the spine and 6 to 8% at the hip in well-controlled studies conducted in the United States and other countries. Chronic Alendronate treatment of postmenopausal women with osteoporosis has been associated with the production of histologically normal bone. Most importantly, increases in bone mineral density and normal bone histology associated with Alendronate therapy have been shown to translate into a significant decrease in the incidence of fractures of the spine, hip and forearm. Although compliance with a daily dosing regimen has been excellent in clinical trials, less frequent dosing regimens may be more desirable for use in clinical practice. Preclinical data in both rat and baboon models treated with Alendronate support similar efficacy with dosing at intervals of up to two weeks. Weekly dosing had not been investigated in postmenopausal women because tolerability of daily orally administered aminobisphosphonates is dose dependent. Therefore, even if the efficacy of weekly oral Alendronate were equivalent to that of daily dosing, the higher daily doses required to deliver the same total cumulative dose might result in a diminished safety and tolerability profile. However, recent preclinical studies of the esophageal irritancy of Alendronate suggest that a weekly exposure to a single high dose is less irritating than daily exposure to multiple lower doses. The once weekly dosing of Alendronate would offer convenience to the patient, should result in similar efficacy, and may offer a safety advantage, although, due to the excellent safety profile of Alendronate 5 mg in clinical trials, it is not anticipated that any difference in safety can be clinically demonstrated. The design and success of the extensive preclinical alendronate development program strongly support the clinical investigation of less frequent oral dosing regimens.
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