Reclast (zoledronic acid) - 4 indications 

Scroll down for information on each indication:

• the treatment of Paget's disease; approved April 2007
• the treatment and prevention of osteoporosis in postmenopausal women; approved August 2007 and May of 2009
• to increase bone mass in men with osteoporosis; approved December of 2008
• for glucocorticoid-induced osteoporosis in patients expected to be on glucocorticoids for at least 12 months; approved March of 2009

General Information

Reclast (zoledronic acid) is a bisphosphonic acid inhibitor of osteoclastic bone resorption. Once administered, it rapidly moves to bone and preferentially localizes at sites of high bone turnover.

Reclast is specifically indicated for the following:

• the treatment and prevention of osteoporosis in postmenopausal women
• to increase bone mass in men with osteoporosis
• for the treatment and prevention of glucocorticoid-induced osteoporosis in men and women who are either initiating or continuing systemic glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and who are expected to remain on glucocorticoids for at least 12 months
• the treatment of Paget's disease of bone in men and women

Reclast is supplied as a sterile solution designed for intravenous infusion. Reclast injection must be administered as an intravenous infusion over no less than 15 minutes. Scroll down for specific dosing/administration for each indication.

Mechanism of Action

Reclast (zoledronic acid) is a bisphosphonate and acts primarily on bone. It is an inhibitor of osteoclast-mediated bone resorption. The selective action of bisphosphonates on bone is based on their high affinity for mineralized bone. Intravenously administered zoledronic acid rapidly partitions to bone and localizes preferentially at sites of high bone turnover. The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate synthase. The relatively long duration of action of zoledronic acid is attributable to its high binding affinity to bone mineral.

Side Effects

Adverse effects associated with the use of Reclast may include, but are not limited to, the following:

• pyrexia
• myalgia
• headache
• arthralgia
• pain in extremity
• flu-like illness
• nausea
• vomiting
• diarrhea
• eye inflammation

Indication 1 - the treatment of Paget's disease

approved April 2007

Dosing/Administration

The recommended dose is a 5 mg infusion. The infusion time must not be less than 15 minutes given over a constant infusion rate.

Clinical Trial Results

The FDA approval of Relast was based on the results of two 6- month randomized, double blind trials. Subjects enrolled in the studies received one infusion of 5-mg Reclast or oral daily doses of 30 mg-risedronate for 2 months. 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. Combined data showed that 96% of the subjects treated with Reclast achieved therapeutic response compared to 74% of those treated with risedronate. At six months, 89% of the Reclast treated subjects achieved normalization of SAP levels versus 58% of those treated with risedronate. In subjects who had previously received treatment with oral bisphosphonates, 96% reached therapeutic response rates compared to 55% for risedronate. In treatment naïve subjects, therapeutic response to Reclast was 98% compared to 86% of those receiving risedronate. In subjects with symptomatic pain at screening, therapeutic response rates were 94% and 70% for Reclast and risedronate respectively. For subjects without pain at screening, therapeutic response rates were 100% and 82% for Reclast and risedronate respectively.

Indication 2 - the treatment and prevention of osteoporosis in postmenopausal women

approved August 2007 and May of 2009

Dosing/Administration

• Treatment: The recommended regimen is a 5 mg infusion once a year given intravenously over no less than 15 minutes.
• Prevention: The recommended regimen is a 5 mg infusion given once every 2 years intravenously over no less than 15 minutes

Clinical Trial Results

FDA approval of Reclast was based on the results of a clinical trial. This randomized, double-blind, placebo -controlled, multinational study enrolled 7,736 women aged 65-89 years with osteoporosis. The subjects were stratified into two groups Stratum I: no concomitant use of osteoporosis therapy or Stratum II: baseline concomitant use of osteoporosis therapies which included calcitonin, raloxifene, tamoxifen and hormone replacement therapy. Reclast was administered once a year for three consecutive years, as a single 5 mg dose in 100 mL solution infused over at least 15 minutes, for a total of three doses. All subjects received 1000 to 1500 mg of elemental calcium plus 400 to 1200 IU of vitamin D supplementation per day. The subjects in Stratum I were evaluated annually for incidence of vertebral fractures. The subjects in Stratum I and II were evaluated for the incidence of hip and other clinical fractures. The primary endpoints were the incidence of morphometric vertebral fractures at 3 years and the incidence of hip fractures over a median duration of 3 years.

Effect on vertebral fractures over three years
Reclast significantly reduced the incidence of new vertebral fractures over three years compared to placebo. In the Reclast arm, there was a 3.3% rate of at least one new vertebral fracture versus 10.9% in the placebo arm (p <0.0001) for a 7.6% absolute reduction in fracture incidence and 70% reduction in fracture incidence.

Effect on hip fracture over three years
Reclast demonstrated a 1.1% absolute reduction and 41% relative reduction in the risk of hip fractures over a median duration of 3 years. The hip fracture event rate was 1.4% for Reclast -treated subjects compared to 2.5% for placebo -treated subjects.

Reclast also had a positive effect over placebo in the following areas:

Bone Mineral Density
Reclast significantly increased BMD at the lumbar spine, total hip and femoral neck, relative to treatment with placebo at time points 12, 24, and 36 months. Treatment with Reclast resulted in a 6.7% increase in BMD at the lumbar spine, 6.0 % at the total hip, and 5.1% at the femoral neck, over 3 years as compared to placebo.

Bone Histology
Bone biopsy specimens were obtained between months 33 and 36 from 82 subjects treated with 3 annual doses of Reclast. Qualitative, quantitative and micro CT assessments showed bone of normal architecture and quality without mineralization defects.

Effect on Height
Over the three-year study standing height was measured annually using a stadiometer. The Reclast group revealed less height loss compared to placebo (4.2 mm vs. 7.0 mm, respectively (p<0.001)).

Indication 3 - to increase bone mass in men with osteoporosis

approved December of 2008

Dosing/Administration

The recommended regimen is a 5 mg infusion once a year given intravenously over no less than 15 minutes.

Clinical Trial Results

The efficacy and safety of Reclast in men with osteoporosis or significant osteoporosis secondary to hypogonadism, was assessed in a randomized, multicenter, double-blind, active controlled, study of 302 men aged 25 to 86 years (mean age of 64). The duration of the trial was two years. Patients were randomized to either Reclast, which was administered once annually as a 5 mg dose in 100 mL infused over 15 minutes for a total of up to two doses, or to an oral weekly bisphosphonate (active control) for up to two years. All participants received 1000 mg of elemental calcium plus 800 to 1000 international units of vitamin D supplementation per day.

Effect on Bone Mineral Density: An annual infusion of Reclast was non-inferior to the oral weekly bisphosphonate active control based on the percentage change in lumbar spine BMD at Month 24 relative to baseline (Reclast: 6.1% increase; active control: 6.2% increase).

Indication 4 - for glucocorticoid-induced osteoporosis in patients expected to be on glucocorticoids for at least 12 months

approved March of 2009

Dosing/Administration

The recommended regimen is a 5 mg infusion once a year given intravenously over no less than 15 minutes.

Clinical Trial Results

The efficacy and safety of Reclast to prevent and treat glucocorticoid-induced osteoporosis (GIO) was assessed in a randomized, multicenter, double-blind, stratified, active controlled study of 833 men and women aged 18 to 85 years (mean age of 54.4 years) treated with greater than or equal to 7.5 mg/day oral prednisone (or equivalent). Patients were stratified according to the duration of their pre-study corticosteroid therapy: less than or equal to 3 months prior to randomization (prevention subpopulation), and greater than 3 months prior to randomization (treatment subpopulation). The duration of the trial was one year. Patients were randomized to either Reclast, which was administered once as a 5 mg dose in 100 mL infused over 15 minutes, or to an oral daily bisphosphonate (active control) for one year. All participants received 1000 mg of elemental calcium plus 400 to 1000 international units of vitamin D supplementation per day. In the GIO treatment subpopulation, Reclast demonstrated a significant mean increase in lumbar spine BMD compared to the active control at one year (Reclast 4.1%, active control 2.7%) with a treatment difference of 1.4%. In the GIO prevention subpopulation, Reclast demonstrated a significant mean increase in lumbar spine BMD compared to active control at one year (Reclast 2.6%, active control 0.6%) with a treatment difference of 2.0%.