"Sept. 9, 2011 -- Labels on bisphosphonates, a type of medication used to treat and prevent osteoporosis, should further clarify how long patients can take them, an FDA advisory panel voted today.
But the panel backed off giving any sp"...
Mechanism of Action
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.
In the osteoporosis treatment trial, the effect of Reclast treatment on markers of bone resorption (serum beta-Ctelopeptides [b-CTx]) and bone formation (bone specific alkaline phosphatase [BSAP], serum N-terminal propeptide of type I collagen [P1NP]) was evaluated in patients (subsets ranging from 517 to 1246 patients) at periodic intervals. Treatment with a 5 mg annual dose of Reclast reduces bone turnover markers to the pre-menopausal range with an approximate 55% reduction in b-CTx, a 29% reduction in BSAP and a 52% reduction in P1NP over 36 months. There was no progressive reduction of bone turnover markers with repeated annual dosing.
Pharmacokinetic data in patients with osteoporosis and Paget's disease of bone are not available.
Single or multiple (q 28 days) 5-minute or 15-minute infusions of 2, 4, 8 or 16 mg zoledronic acid were given to 64 patients with cancer and bone metastases. The post-infusion decline of zoledronic acid concentrations in plasma was consistent with a triphasic process showing a rapid decrease from peak concentrations at end-of-infusion to less than 1% of Cmax 24 hours post infusion with population half-lives of t½ α 0.24 hour and t½ β 1.87 hours for the early disposition phases of the drug. The terminal elimination phase of zoledronic acid was prolonged, with very low concentrations in plasma between Days 2 and 28 post infusion, and a terminal elimination half-life t½ γ of 146 hours. The area under the plasma concentration versus time curve (AUC0-24h) of zoledronic acid was dose proportional from 2 to 16 mg. The accumulation of zoledronic acid measured over three cycles was low, with mean AUC0-24h ratios for cycles 2 and 3 versus 1 of 1.13 ± 0.30 and 1.16 ± 0.36, respectively.
In vitro and ex vivo studies showed low affinity of zoledronic acid for the cellular components of human blood. In vitro mean zoledronic acid protein binding in human plasma ranged from 28% at 200 ng/mL to 53% at 50 ng/mL.
Zoledronic acid does not inhibit human P450 enzymes in vitro. Zoledronic acid does not undergo biotransformation in vivo. In animal studies, less than 3% of the administered intravenous dose was found in the feces, with the balance either recovered in the urine or taken up by bone, indicating that the drug is eliminated intact via the kidney. Following an intravenous dose of 20 nCi 14C-zoledronic acid in a patient with cancer and bone metastases, only a single radioactive species with chromatographic properties identical to those of parent drug was recovered in urine, which suggests that zoledronic acid is not metabolized.
In 64 patients with cancer and bone metastases on average (± SD) 39 ± 16% of the administered zoledronic acid dose was recovered in the urine within 24 hours, with only trace amounts of drug found in urine post Day 2. The cumulative percent of drug excreted in the urine over 0-24 hours was independent of dose. The balance of drug not recovered in urine over 0-24 hours, representing drug presumably bound to bone, is slowly released back into the systemic circulation, giving rise to the observed prolonged low plasma concentrations. The 0-24 hour renal clearance of zoledronic acid was 3.7 ± 2.0 L/h.
Zoledronic acid clearance was independent of dose but dependent upon the patient's creatinine clearance. In a study in patients with cancer and bone metastases, increasing the infusion time of a 4 mg dose of zoledronic acid from 5 minutes (n=5) to 15 minutes (n=7) resulted in a 34% decrease in the zoledronic acid concentration at the end of the infusion ([mean ± SD] 403 ± 118 ng/mL vs. 264 ± 86 ng/mL) and a 10% increase in the total AUC (378 ± 116 ng x h/mL vs. 420 ± 218 ng x h/mL). The difference between the AUC means was not statistically significant.
Pediatrics: Reclast is not indicated for use in children [see Pediatric Use].
Geriatrics: The pharmacokinetics of zoledronic acid was not affected by age in patients with cancer and bone metastases whose age ranged from 38 years to 84 years.
Race: The pharmacokinetics of zoledronic acid was not affected by race in patients with cancer and bone metastases.
Hepatic Impairment: No clinical studies were conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of zoledronic acid.
Renal Impairment: The pharmacokinetic studies conducted in 64 cancer patients represented typical clinical populations with normal to moderately-impaired renal function. Compared to patients with creatinine clearance greater than 80 mL/min (N=37), patients with creatinine clearance = 50-80 mL/min (N=15) showed an average increase in plasma AUC of 15%, whereas patients with creatinine clearance = 30-50 mL/min (N=11) showed an average increase in plasma AUC of 43%. No dosage adjustment is required in patients with a creatinine clearance of greater than or equal to 35 mL/min. Reclast is contraindicated in patients with creatinine clearance less than 35 mL/min and in those with evidence of acute renal impairment due to an increased risk of renal failure [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Use in Specific Populations].
Bone Safety Studies
Zoledronic acid is a potent inhibitor of osteoclastic bone resorption. In the ovariectomized rat, single IV doses of zoledronic acid of 4-500 μg/kg (less than 0.1 to 3.5 times human exposure at the 5 mg intravenous dose, based on a mg/m² comparison) suppressed bone turnover and protected against trabecular bone loss, cortical thinning and the reduction in vertebral and femoral bone strength in a dose-dependent manner. At a dose equivalent to human exposure at the 5 mg intravenous dose, the effect persisted for 8 months, which corresponds to approximately 8 remodeling cycles or 3 years in humans.
In ovariectomized rats and monkeys, weekly treatment with zoledronic acid dose-dependently suppressed bone turnover and prevented the decrease in cancellous and cortical BMD and bone strength, at yearly cumulative doses up to 3.5 times the intravenous human dose of 5 mg, based on a mg/m² comparison. Bone tissue was normal and there was no evidence of a mineralization defect, no accumulation of osteoid, and no woven bone.
Reproductive and Developmental Toxicology
In female rats given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation, the number of stillbirths was increased and survival of neonates was decreased in the mid- and high-dose groups (greater than or equal to 0.3 times the anticipated human systemic exposure following a 5 mg intravenous dose, based on an AUC comparison). Adverse maternal effects were observed in all dose groups (greater than or equal to 0.1 times the human systemic exposure following a 5 mg intravenous dose, based on an AUC comparison) and included dystocia and periparturient mortality in pregnant rats allowed to deliver. Maternal mortality was considered related to drug-induced inhibition of skeletal calcium mobilization, resulting in periparturient hypocalcemia. This appears to be a bisphosphonate class effect.
In pregnant rats given daily subcutaneous dose of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg during gestation, adverse fetal effects were observed in the mid- and high-dose groups (about 2 and 4 times human systemic exposure following a 5 mg intravenous dose, based on an AUC comparison). These adverse effects included increases in pre- and post-implantation losses, decreases in viable fetuses, and fetal skeletal, visceral, and external malformations. Fetal skeletal effects observed in the high-dose group included unossified or incompletely ossified bones, thickened, curved or shortened bones, wavy ribs, and shortened jaw. Other adverse fetal effects observed in the high-dose group included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were also observed in the low-dose group (about 1.2 times the anticipated human systemic exposure, based on an AUC comparison). Signs of maternal toxicity were observed in the high-dose group and included reduced body weights and food consumption, indicating that maximal exposure levels were achieved in this study.
In pregnant rabbits given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day during gestation (at doses less than or equal to 0.4 times the anticipated human systemic exposure following a 5 mg intravenous dose, based on a mg/m² comparison) no adverse fetal effects were observed. Maternal mortality and abortion occurred in all treatment groups (at doses greater than or equal to 0.04 times the human 5 mg intravenous dose, based on a mg/m² comparison). Adverse maternal effects were associated with, and may have been caused by, drug-induced hypocalcemia.
Treatment of Postmenopausal Osteoporosis
Study 1: The efficacy and safety of Reclast in the treatment of postmenopausal osteoporosis was demonstrated in Study 1, a randomized, double-blind, placebo-controlled, multinational study of 7736 women aged 65-89 years (mean age of 73) with either: a femoral neck BMD T-score less than or equal to -1.5 and at least two mild or one moderate existing vertebral fracture(s); or a femoral neck BMD T-score less than or equal to -2.5 with or without evidence of an existing vertebral fracture(s). Women 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, but excluded other bisphosphonates.
Women enrolled in Stratum I (n=5661) were evaluated annually for incidence of vertebral fractures. All women (Strata I and II) were evaluated for the incidence of hip and other clinical fractures. 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 women received 1000 to 1500 mg of elemental calcium plus 400 to 1200 international units of vitamin D supplementation per day.
The two primary efficacy variables were the incidence of morphometric vertebral fractures at 3 years and the incidence of hip fractures over a median duration of 3 years. The diagnosis of an incident vertebral fracture was based on both qualitative diagnosis by the radiologist and quantitative morphometric criterion. The morphometric criterion required the dual occurrence of 2 events: a relative height ratio or relative height reduction in a vertebral body of at least 20%, together with at least a 4 mm absolute decrease in height.
Effect on Vertebral Fractures
Reclast significantly decreased the incidence of new vertebral fractures at one, two, and three years as shown in Table 5.
Table 5: Proportion of Patients with New Morphometric
|Outcome||Reclast (%)||Placebo (%)||Absolute Reduction in Fracture Incidence % (95% CI)||Relative Reduction in Fracture Incidence % (95% CI)|
|At least one new vertebral fracture (0-1 year)||1.5||3.7||2.2 (1.4, 3.1)||60 (43, 72)*|
|At least one new vertebral fracture (0-2 years)||2.2||7.7||5.5 (4.4, 6.6)||71 (62, 78)*|
|At least one new vertebral fracture (0-3 years)||3.3||10.9||7.6 (6.3, 9.0)||70 (62, 76)*|
|* p < 0.0001|
The reductions in vertebral fractures over three years were consistent (including new/worsening and multiple vertebral fractures) and significantly greater than placebo regardless of age, geographical region, baseline body mass index, number of baseline vertebral fractures, femoral neck BMD T-score, or prior bisphosphonate usage.
Effect on Hip Fracture over 3 years
Reclast demonstrated a 1.1% absolute reduction and 41% relative reduction in the risk of hip fractures over a median duration of follow-up of 3 years. The hip fracture event rate was 1.4% for Reclast-treated patients compared to 2.5% for placebo-treated patients.
Figure 1: Cumulative Incidence of Hip Fracture Over 3
The reductions in hip fractures over three years were greater for Reclast than placebo regardless of femoral neck BMD T-score.
Effect on All Clinical Fractures
Reclast demonstrated superiority to placebo in reducing the incidence of all clinical fractures, clinical (symptomatic) vertebral and non-vertebral fractures (excluding finger, toe, facial, and clinical thoracic and lumbar vertebral fractures). All clinical fractures were verified based on the radiographic and/or clinical evidence. A summary of results is presented in Table 6.
Table 6: Between–Treatment
Comparisons of the Incidence of Clinical Fracture Variables Over 3 Years
Event Rate n (%)+
Event Rate n (%)+
|Absolute Reduction in Fracture Incidence % (95% CI)+||Relative Risk Reduction in Fracture Incidence % (95% CI)|
|Any clinical fracture 1||308 (8.4)||456 (12.8)||4.4 (3.0, 5.8)||33 (23, 42)**|
|Clinical vertebral fracture 2||19 (0.5)||84 (2.6)||2.1 (1.5, 2.7)||77 (63, 86)**|
|Non-vertebral fracture 3||292 (8.0)||388 (10.7)||2.7 (1.4, 4.0)||25 (13, 36)*|
|*p-value < 0.001, **p-value < 0.0001
+ Event rates based on Kaplan-Meier estimates at 36 months
1 Excluding finger, toe, and facial fractures
2 Includes clinical thoracic and clinical lumbar vertebral fractures
3 Excluding finger, toe, facial, and clinical thoracic and lumbar vertebral fractures
Effect on Bone Mineral Density (BMD)
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 biopsy specimens were obtained between Months 33 and 36 from 82 postmenopausal patients with osteoporosis treated with 3 annual doses of Reclast. Of the biopsies obtained, 81 were adequate for qualitative histomorphometry assessment, 59 were adequate for partial quantitative histomorphometry assessment, and 38 were adequate for full quantitative histomorphometry assessment. Micro CT analysis was performed on 76 specimens. Qualitative, quantitative and micro CT assessments showed bone of normal architecture and quality without mineralization defects.
Effect on Height
In the 3-year osteoporosis 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]).
Study 2: The efficacy and safety of Reclast in the treatment of patients with osteoporosis who suffered a recent low-trauma hip fracture was demonstrated in Study 2, a randomized, double-blind, placebo-controlled, multinational endpoint study of 2127 men and women aged 50-95 years (mean age of 74.5). Concomitant osteoporosis therapies excluding other bisphosphonates and parathyroid hormone were allowed. Reclast was administered once a year as a single 5 mg dose in 100 mL solution, infused over at least 15 minutes. The study continued until at least 211 patients had confirmed clinical fractures in the study population. Vitamin D levels were not routinely measured but a loading dose of vitamin D (50,000 to 125,000 international units orally or IM) was given to patients and they were started on 1000 to 1500 mg of elemental calcium plus 800 to 1200 international units of vitamin D supplementation per day for at least 14 days prior to the study drug infusions. The primary efficacy variable was the incidence of clinical fractures over the duration of the study.
Reclast significantly reduced the incidence of any clinical fracture by 35%. There was also a 46% reduction in the risk of a clinical vertebral fracture (Table 7).
Table 7: Between-Treatment Comparisons of the
Incidence of Key Clinical Fracture Variables
Event Raten (%)+
Event Raten (%)+
|Absolute Reduction in Fracture Incidence % (95% CI) +||Relative Risk Reduction in Fracture Incidence % (95% CI)|
|Any clinical fracture1||92 (8.6)||139 (13.9)||5.3(2.3, 8.3)||35(16, 50)**|
|Clinical vertebral fracture2||21 (1.7)||39 (3.8)||2.1(0.5, 3.7)||46(8, 68)*|
|*p-value < 0.05, **p-value < 0.005
+ Event rates based on Kaplan-Meier estimates at 24 months
1 Excluding finger, toe and facial fractures
2 Including clinical thoracic and clinical lumbar vertebral fractures
Effect on Bone Mineral Density (BMD)
Reclast significantly increased BMD relative to placebo at the hip and femoral neck at all timepoints (12, 24, and 36 months). Treatment with Reclast resulted in a 6.4% increase in BMD at the total hip and a 4.3% increase at the femoral neck over 36 months as compared to placebo.
Prevention of Postmenopausal Osteoporosis
The efficacy and safety of Reclast in postmenopausal women with osteopenia (low bone mass) was assessed in a 2-year randomized, multi-center, double-blind, placebo-controlled study of 581 postmenopausal women aged greater than or equal to 45 years, who were stratified by years since menopause: Stratum I women less than 5 years from menopause (n=224); Stratum II women greater than or equal to 5 years from menopause (n=357). Patients within Stratum I and II were randomized to one of three treatment groups: (1) Reclast given at randomization and at Month 12 (n=77) in Stratum I and (n=121) in Stratum II; (2) Reclast given at randomization and placebo at Month 12 (n=70) in Stratum I and (n=111) in Stratum II; and (3) Placebo given at randomization and Month 12 (n=202). Reclast was administered as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. All women received 500 to 1200 mg elemental calcium plus 400 to 800 international units vitamin D supplementation per day. The primary efficacy variable was the percent change of BMD at 24 Months relative to baseline.
Effect on Bone Mineral Density (BMD)
Reclast significantly increased lumbar spine BMD relative to placebo at Month 24 across both strata. Reclast given once at randomization (and placebo given at Month 12) resulted in 4.0% increase in BMD in Stratum I patients and 4.8% increase in Stratum II patients over 24 months. Placebo given at randomization and at Month 12 resulted in 2.2% decrease in BMD in Stratum I patients and 0.7% decrease in BMD in Stratum II patients over 24 months. Therefore, Reclast given once at randomization (and placebo given at Month 12) resulted in a 6.3% increase in BMD in Stratum I patients and 5.4% increase in Stratum II patients over 24 months as compared to placebo (both p < 0.0001).
Reclast also significantly increased total hip BMD relative to placebo at Month 24 across both strata. Reclast given once at randomization (and placebo given at Month 12) resulted in 2.6% increase in BMD in Stratum I patients and 2.1% in Stratum II patients over 24 months. Placebo given at randomization and at Month 12 resulted in 2.1% decrease in BMD in Stratum I patients and 1.0% decrease in BMD in Stratum II patients over 24 months. Therefore, Reclast given once at randomization (and placebo given at Month 12) resulted in a 4.7% increase in BMD in Stratum I patients and 3.2% increase in Stratum II patients over 24 months as compared to placebo (both p < 0.0001).
Osteoporosis in Men
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 25-86 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 (BMD)
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).
Treatment and Prevention of Glucocorticoid-Induced Osteoporosis
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 18-85 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.
Effect on Bone Mineral Density (BMD)
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% (p < 0.001). 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% (p < 0.001).
Bone biopsy specimens were obtained from 23 patients (12 in the Reclast treatment group and 11 in the active control treatment group) at Month 12 treated with an annual dose of Reclast or daily oral active control. Qualitative assessments showed bone of normal architecture and quality without mineralization defects. Apparent reductions in activation frequency and remodeling rates were seen when compared with the histomorphometry results seen with Reclast in the postmenopausal osteoporosis population. The long-term consequences of this degree of suppression of bone remodeling in glucocorticoid-treated patients is unknown.
Treatment of Paget's Disease of Bone
Reclast 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 Reclast 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 Reclast 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 Reclast-treated patients achieved a therapeutic response as compared with 74% (127/171) of patients treated with risedronate. Most Reclast patients achieved a therapeutic response by the Day 63 visit. In addition, at 6 months, 89% (156/176) of Reclast-treated patients achieved normalization of SAP levels, compared to 58% (99/171) of patients treated with risedronate (p < 0.0001) (see Figure 2).
Figure 2: Therapeutic Response/Serum Alkaline
Phosphatase (SAP) Normalization Over Time
The therapeutic response to Reclast was similar across demographic and disease-severity groups defined by gender, age, previous bisphosphonate use, and disease severity. At 6 months, the percentage of Reclast-treated patients who achieved therapeutic response was 97% and 95%, respectively, in each of the baseline disease severity subgroups (baseline SAP less than 3xULN, greater than or equal to 3xULN) 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 Reclast 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 na´ve to previous treatment, a greater therapeutic response was also observed with Reclast (98%) relative to risedronate (86%). In patients with symptomatic pain at screening, therapeutic response rates were 94% and 70% for Reclast and risedronate respectively. For patients without pain at screening, therapeutic response rates were 100% and 82% for Reclast and risedronate respectively.
Bone histology was evaluated in 7 patients with Paget's disease 6 months after being treated with Reclast 5 mg. Bone biopsy results showed bone of normal quality with no evidence of impaired bone remodeling and no evidence of mineralization defect.
Last reviewed on RxList: 5/6/2013
This monograph has been modified to include the generic and brand name in many instances.
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