National PBM Monograph Template



National PBM Drug Monograph

Zoledronic acid Injection (Reclast)

VHA Pharmacy Benefits Management Service and the Medical Advisory Panel

November 2008; Updated September 2009 (See Addendum)

The purpose of VACO PBM drug monographs is to provide a comprehensive drug review for making formulary decisions. These documents will be updated when new clinical data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current.

Executive Summary:

• Zoledronic acid (ZA), like other bisposphonates, is an inhibitor of osteoclastic-mediated bone resorption.

• Zoledronic acid has FDA approved labeling for:

o Treatment of osteoporosis in postmenopausal women including patients at high risk of fracture, defined as a recent low-trauma hip fracture Prevention of osteoporosis in postmenopausal women

o Treatment to increase bone mass in men with osteoporosis

o Prevention and treatment of gluococorticoid –induced osteoporosis in patients expected to be on glucocorticoids for at least 12-months

o Treatment of Paget’s disease of bone in men and women.

• Dose: A single 5 mg infusion administered over 15 minutes

o Once a year for the treatment of osteoporosis in postmenopausal women and men

o Once a year for the prevention and treatment of gluococorticoid –induced osteoporosis

o Every 2-years for the prevention of osteoporosis in postmenopausal women

• Zoledronic acid has demonstrated a faster onset of action as measured by suppression of biomarkers of bone turnover and formation.

• The HORIZON Pivotal Fracture Trial demonstrated that over 3-year period an annual 5 mg ZA infusion significantly reduced the risk of vertebral, hip and other fractures in postmenopausal women.

• The HORIZON Recurrent Fracture Trial concluded that a yearly infusion of ZA within 90 days of repair of a low-trauma hip fracture was associated with reduced risk for new clinical fractures with improved survival.

• In a pooled analysis of 2 six month clinical trials with 18 month extensions, a single 5 mg infusion of ZA produced a more rapid, more complete and longer therapeutic response than risedronate in patients with Paget’s disease.

• Zoledronic acid is not recommended for patients with a creatinine clearance 2 standard deviations (SD) below a T-score of -2. Outcome was assessed by changes in BMD (lumbar spine, non-dominant proximal femur and forearm, and total body) as measured by dual-energy x-ray absorptiometry (DXA) and changes in biomarkers of bone turnover, NTX and β-CTX, and bone formation, BSAP and serum osteocalcin, at baseline, 6, 9 and 12 months.

Postmenopausal women between 45-80 years of age were randomized in a double-blind manner to one of six treatment arms: ZA infusion of 0.25 mg, 0.5 mg, or 1 mg every 3 months; 2 mg every 6 months for 2 doses; a single 4 mg dose; or placebo every 3 months. All treatment arms received an infusion every 3 months of either active medication or placebo.

Three hundred sixteen of the 351 women randomized completed the trial. Baseline characteristics did not differ significantly between the six treatment groups. The percent changes in BMD at the lumbar spine (4.3% - 5.1% at 12 months) and femoral neck (3.1% - 3.5% at 12 months) were significantly greater in all ZA groups than placebo at all time points. There were no significant differences between any of the ZA groups. Differences in changes in BMD at the distal radius were smaller (0.8% - 1.6% at 12 months), yet significant from placebo except between placebo and ZA 0.25 mg. Similar small, yet significant, differences were reported for changes in total body BMD (0.9% - 1.3% at 12 months) except between ZA 0.5 mg and placebo. Biomarkers of bone turnover and bone formation were significantly suppressed by all doses of ZA.

Speed of Onset: ZA vs. Alendronate3

In order to compare the speed of onset of action between a single 5 mg dose of ZA and a weekly 70 mg dose of alendronate (for 24-weeks), investigators conducted an international, multicenter, randomized, double-blind, double-dummy, active controlled clinical trial in postmenopausal women between 45 and 79 years of age. Study entry required a T score < -2 at the lumbar spine or femoral neck within 3 months of screening. Subjects who’d taken a bisphosphonate within the previous 2 years were ineligible unless their lifetime exposure was less than 8 weeks and there had been no exposure in the 6 months prior to randomization. Subjects who’d ever taken sodium fluoride, strontium ranelate or parathyroid hormone were ineligible as were those who’d been treated with raloxifene, calcitonin, tibolone or hormone replacement therapy (HRT) within 6 months prior to randomization or whose CrCl was less than 30 mL/min. Subjects were randomized in a 1:1 ratio of ZA to alendronate. All subjects received 1000 mg/day of elemental calcium and 400 IU/day of vitamin D during the study.

Change from baseline in biochemical markers were used as outcome measures, specifically, NTX and β-CTX were used to assess the rate of bone resorption while BSAP functioned as a measure of bone formation. Urine NTX and serum β-CTX were measured at baseline and on weeks 1, 2, 4, 8, 12, and 24; serum BSAP was measured at baseline and weeks 4, 12 and 24. The study’s primary endpoint was the change in NTX after the first-week of treatment (one week after the dose of ZA or the initial dose of alendronate). Patient preference to treatment modality and dyspepsia symptoms were secondary outcome measures. An intention-to-treat analytical approach was employed.

One hundred twenty-eight subjects were randomized: 69 to ZA and 59 to placebo. Compliance exceeded 85% in both groups with respect to oral alendronate or oral placebo. Baseline demographic, NTX, β-CTX, and BSAP values did not differ significantly. At the one week point, the mean NTX concentration was significantly lower in the ZA group than the alendronate group, p ................
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