Extended Treatment Effects with Zoledronic Acid Based on Poster 1070 “The Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT)” Saturday, October 16, 2010 ASBMR 2010 Toronto, Ontario

Background and Method Zoledronic acid (ZA) 5 mg used annually for 3 years has been shown to be effective in increasing BMD and decreasing fractures The extension trial of HORIZON-PFT evaluated the effect of continuing ZA for 3 more years All patients eligible for the extension trial had to have received all 3 annual infusions of ZA A total of 1233 women were randomized to either ZA for 3 more years (Z6 group) or to placebo (Z3P3 group) Baseline characteristics of the two groups were similar with about half of each group having bone mineral density (BMD) T-scores at the femoral neck <-2.5 and about 60% having 1 or more vertebral fractures.

End Points Primary Outcome Measure: Per cent change in BMD of femoral neck at year 6 relative to year 3 Secondary Outcome Measures: Change from baseline of biochemical markers of bone turnover at different time points Per cent change from baseline in BMD of spine and distal radius at year 4.5 and 6 Per cent change from baseline in BMD of femoral neck, total hip and trochanter at different time points Proportion of patients with new vertebral fractures and incidence of clinical fracture Bone biopsy to evaluate bone quality Evaluation of safety parameters (renal function, laboratory parameters, adverse event profile)

Results Mean per cent change in femoral neck BMD over the 3-year extension remained constant in the Z6 group compared with a slight drop in the Z3P3 group for a between-group difference at year 6 of 1.04% (P=0.0009)

Results Mean per cent changes in total hip BMD were similar to those at the femoral neck at 4.2% for the Z6 group vs. 2.8% for the Z3P3 group Over the 6 years of treatment, the Z6 group had a significant mean femoral neck BMD increase of 4.5% vs. 3.1% for the Z3P3 group Mean lumbar spine BMD increased by 12% from baseline for the Z6 group vs. 10% from baseline in the Z3P3 which was not statistically significant Biochemical markers remained constant in the Z6 group but rose slightly in the Z3P3 group

Results The morphometric verterbral fracture rate was 6.2% in the Z3P3 group; this rate was reduced by about 52% in the group receiving ZA for 6 years Only 11 clinical vertebral fractures were seen during the extension study and there was no difference between the 2 groups There was no difference in non-vertebral fracture rates between the 2 groups A total of 15 hip fractures occurred during the extension study and there was no difference in hip fracture rates between the 2 groups

Adverse Events (AEs) Overall AEs were similar in the 2 groups; serious AEs were numerically more frequent in the Z6 group but this difference was not statistically significant No long-term effect on renal function was observed and there were no differences in CV event rates between the 2 groups Only 1 case of osteonecrosis of the jaw occurred in the Z6 group and there were no atypical fractures in either group Hypertension was almost twice as common in the Z3P3 group vs. the Z6 group

Conclusions A comparable safety profile was observed in the 3-year extension with the first 3-year data After 3 years of ZA therapy, it may be beneficial for some women, particularly those at high risk for vertebral fracture, to continue on ZA In making decisions about long-term use of BPs, it is important to individualize treatment decisions and to try to identify women for whom a drug holiday may be appropriate