Safety and Efficacy Trial With Zoledronic Acid for the Treatment of Paget's Disease of Bone, Including an Extended Observation Period

• Relative Change in Serum Alkaline Phosphatase in U/L at Day 28 [ Time Frame: Baseline and 28 days ] [ Designated as safety issue: No ]
  The percent change in serum alkaline phosphatase from baseline to Day 28 was measured.
• Relative Change in Serum C-telopeptide (CTx) in ng/mL at Day 10 [ Time Frame: Baseline and day 10 ] [ Designated as safety issue: No ]
  The percent change in serum C-telopeptide from baseline to Day 10 was measured.
• Relative Change in Urine α-CTx in ug/mmol at Day 10 [ Time Frame: Baseline and day 10 ] [ Designated as safety issue: No ]
  The percent change in urine α-CTx from baseline to Day 10 was measured.
• Time to First Therapeutic Response [ Time Frame: 182 days ] [ Designated as safety issue: No ]
  Therapeutic response was defined as a reduction of at least 75% from baseline in serum alkaline phosphatase excess (difference between measured level and midpoint to the normal range) or normalization of serum alkaline phosphatase.
• Number of Patients Who Achieved Serum Alkaline Phosphatase Normalization at Day 28 [ Time Frame: Day 28 ] [ Designated as safety issue: No ]
  Normalization of serum alkaline phosphatase occurred if the serum alkaline phosphatase measurement fell within the normal range. Central laboratory reference ranges for serum alkaline phosphatase: 31-110 U/L (female & male 20-58 years) and 35-115 U/L (female & male >58 years).
• Change in Pain Severity at Day 182 [ Time Frame: Baseline and day 182 ] [ Designated as safety issue: No ]
  Change in pain severity score from Brief Pain Inventory-Short Form (BPI-SF). This scale values are 0 to 10, a lower score means little to no pain while a higher score means greater pain.
• Change in Pain Interference at Day 182 [ Time Frame: Baseline and day 182 ] [ Designated as safety issue: No ]
  Change in pain interference score from Brief Pain Inventory-Short Form (BPI-SF). This scale values are 0 to 10, a lower score means little to no pain while a higher score means greater pain.
• Number of Participants With a Loss of Therapeutic Response During the Extended Observation Period [ Time Frame: 8 years was the maximum ] [ Designated as safety issue: No ]
  Extended observation period. A therapeutic response is defined as a reduction of at least 75% from baseline in serum alkaline phosphatase excess or normalization of serum alkaline phosphatase.
• Number of Participants With a Partial Disease Relapse During the Extended Observation Period [ Time Frame: 8 years was the maximum ] [ Designated as safety issue: No ]
  Extended observation period. A partial disease relapse was defined as an increase in serum alkaline phosphatase >= 50% from the serum alkaline phosphatase measurement at Month 6 and at least 1.25 times the upper normal limit.
• Number of Participants With a Disease Relapse During the Extended Observation Period [ Time Frame: 8 years was maximum ] [ Designated as safety issue: No ]
  Extended observation period. A disease relapse was defined as the occurrence of a serum alkaline phosphatase level that was >= 80% of baseline serum alkaline phosphatase value.

The primary objective of this core study was to show non-inferiority of zoledronic acid to risedronate, with respect to the proportion of patients who achieved therapeutic response. The extended observation period included participants of the core study who responded to treatment.

• Drug: zoledronic acid
  5 mg zoledronic acid in 5 mL of sterile water for infusion
• Drug: placebo to zoledronic acid
  5 mL of sterile water for infusion
• Drug: Risedronate
  30mg oral tablets overencapsulated to match the placebo capsules
• Drug: Placebo to risedronate
  oral capsules
• Drug: Calcium and vitamin D supplements
  Calcium and vitamin D supplements were supplied

• Experimental: Zoledronic acid and placebo to risedronate
  Participants received zoledronic acid 5.0 mg i.v. infusion one dose, 60 days of oral placebo to risedronate, calcium 500mg bid and vitamin D 400 to 1000 IU daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.
  Interventions:

  • Drug: zoledronic acid
  • Drug: Placebo to risedronate
  • Drug: Calcium and vitamin D supplements
• Active Comparator: Risedronate and placebo to zoledronic acid
  Participants received 60 days of oral risedronate 30 mg, one i.v. infusion of placebo to zoledronic acid infusion, calcium 500mg bid and vitamin d 400 to 1000 IU daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.
  Interventions:

  • Drug: placebo to zoledronic acid
  • Drug: Risedronate
  • Drug: Calcium and vitamin D supplements

Inclusion Criteria:

• 30 years or older
• SAP 2 times ULN
• Confirmed diagnosis of Paget's disease of the bone (by x-ray, magnetic resonance imaging, computerized tomography, radioisotope imaging, etc.).
• 90 days washout calcitonin
• 180 day washout bisphosphonate

Exclusion Criteria:

• Allergic reaction to bisphosphonates
• History of upper GI disorders
• History of iritis, uveitis
• Calculated creatinine clearance < 30 ml/min at baseline
• Evidence of vitamin D deficiency

Other protocol-defined inclusion/exclusion criteria may apply.