Therefore, it was considered that the amount of accumulation of bisphosphonate within bone after each single intermittent dose was more than that obtained with continuous administration. It was considerable that the amount of risedronate accumulation is higher in the 75 mg once-monthly group than in the 2.5 mg once-daily group after each single 75 mg once-monthly group treatment. Therefore, each administration of risedronate 75 mg once-monthly, which has a larger accumulation Cabozantinib in bone, is possibly associated with more diffusion in bone than 2.5 mg once-daily administration. Therefore,

it may be possible that this difference of distribution in bone between daily and monthly risedronate administration causes the difference in the prevention of bone fracture, but further research is required to obtain more data. With regard to safety, the frequency of overall AEs, gastrointestinal AEs (which are typical AEs during bisphosphonate therapy), serious AEs, and the number of subjects for whom treatment was discontinued due to AEs, were comparable

in the two treatment groups. The frequency of AEs associated with gastrointestinal symptoms was similar between treatment groups. There was no notable difference in baseline demographics, complications, and medical history between subjects who GKT137831 had developed AEs associated with gastrointestinal symptoms and those who had not. AEs associated with gastrointestinal symptoms developed most frequently during the period from the

initial administration to Day 30; the frequency of new onset of gastrointestinal symptoms tended to decrease thereafter in each of the treatment groups (data not presented). One of the AEs, diarrhea, was remarkable as its frequency was higher in the 75 mg once-monthly group than in the 2.5 mg once-daily group. However, the number of subjects who discontinued due to diarrhea did not differ significantly between the two treatment groups (4 and 5 subjects in the 2.5 mg once-daily and 75 mg once-monthly groups, respectively) and its severity was mild or moderate. Influenza-like illness associated with Org 27569 both IV and oral bisphosphonates is transitory and self-limiting and usually does not recur after subsequent drug administration. This influenza-like illness is referred to as APR [28]. In the current study, AEs potentially associated with APRs only occurred in the 75 mg once-monthly group; the incidence was low, severity was mild or moderate, and these events were not considered to be clinically important. In the multinational (ex-Japan) phase III study, AEs potentially associated with APRs occurred at a similarly low rate as in our study; 1.4% (9/650) of subjects treated with risedronate 150 mg once-monthly and 0.2% (1/642) of subjects treated with 5 mg once-daily [7].