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ZOLEDRONIC ACID INJECTION - FOR INTRAVENOUS INFUSION Clinical Studies (zoledronic acid for injection - FOR INTRAVENOUS INFUSION)

14 CLINICAL STUDIES

14.5 Treatment of Paget's Disease of Bone

Zoledronic acid was studied in male and female patients with moderate to severe Paget's disease of bone, defined as serum alkaline phosphatase level at least twice the upper limit of the age-specific normal reference range at the time of study entry. Diagnosis was confirmed by radiographic evidence.

The efficacy of one infusion of 5 mg zoledronic acid vs. oral daily doses of 30 mg risedronate for 2 months was demonstrated in two identically designed 6-month randomized, double-blind trials. The mean age of patients in the two trials was 70. Ninety-three percent (93%) of patients were Caucasian. Therapeutic response was defined as either normalization of serum alkaline phosphatase (SAP) or a reduction of at least 75% from baseline in total SAP excess at the end of 6 months. SAP excess was defined as the difference between the measured level and midpoint of normal range.

In both trials zoledronic acid demonstrated a superior and more rapid therapeutic response compared with risedronate and returned more patients to normal levels of bone turnover, as evidenced by biochemical markers of formation (SAP, serum N-terminal propeptide of type I collagen [P1NP]) and resorption (serum CTx 1 [cross-linked C-telopeptides of type I collagen] and urine α-CTx).

The 6-month combined data from both trials showed that 96% (169/176) of zoledronic acid-treated patients achieved a therapeutic response as compared with 74% (127/171) of patients treated with risedronate. Most zoledronic acid patients achieved a therapeutic response by the Day 63 visit. In addition, at 6 months, 89% (156/176) of zoledronic acid-treated patients achieved normalization of SAP levels, compared to 58% (99/171) of patients treated with risedronate (p<0.0001) (see Figure 1).

Figure 1. Therapeutic Response/Serum Alkaline Phosphatase (SAP)

The therapeutic response to zoledronic acid was similar across demographic and disease-severity groups defined by gender, age, previous bisphosphonate use, and disease severity. At 6 months, the percentage of zoledronic acid-treated patients who achieved therapeutic response was 97% and 95%, respectively, in each of the baseline disease severity subgroups (baseline SAP less than 3×ULN, greater than or equal to 3×ULN) compared to 75% and 74%, respectively, for the same disease severity subgroups of risedronate-treated patients.

In patients who had previously received treatment with oral bisphosphonates, therapeutic response rates were 96% and 55% for zoledronic acid and risedronate, respectively. The comparatively low risedronate response was due to the low response rate (7/23, 30%) in patients previously treated with risedronate. In patients naïve to previous treatment, a greater therapeutic response was also observed with zoledronic acid (98%) relative to risedronate (86%). In patients with symptomatic pain at screening, therapeutic response rates were 94% and 70% for zoledronic acid and risedronate respectively. For patients without pain at screening, therapeutic response rates were 100% and 82% for zoledronic acid and risedronate respectively.

Bone histology was evaluated in 7 patients with Paget's disease 6 months after being treated with zoledronic acid 5 mg. Bone biopsy results showed bone of normal quality with no evidence of impaired bone remodeling and no evidence of mineralization defect.

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