Aclasta Mechanism of Action

Pharmacotherapeutic group: Bisphosphonate. ATC code: M05 BA08.
PHARMACOLOGY: Mechanism of action (MOA): Zoledronic acid belongs to the class of nitrogen-containing bisphosphonates 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 mineralised bone. Intravenously administered zoledronic acid is rapidly distributed to bone and, like other bisphosphonates, localises preferentially at sites of high bone turnover. The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate synthase, but this does not exclude other mechanisms. The relatively long duration of action of zoledronic acid is attributable to its high binding affinity for the active site of farnesyl pyrophosphate (FPP) synthase and its strong binding affinity to bone mineral.
Pharmacodynamics: Osteoporosis: Aclasta treatment rapidly reduced the rate of bone turnover from elevated postmenopausal levels with the nadir for resorption markers observed at 7 days, and for formation markers at 12 weeks. Thereafter bone markers stabilized within the premenopausal range. There was no progressive reduction of bone turnover markers with repeated annual dosing.
In long-term animal studies, zoledronic acid inhibits bone resorption without adversely affecting bone formation, mineralisation or the mechanical properties of bone. Histomorphometric data from long-term rat and monkey experiments showed the typical response of bone to an anti-resorptive agent with a dose-dependent reduction in osteoclastic activity and activation frequency of new remodelling sites in both trabecular and Haversian bone. Continuing bone remodelling was observed in bone samples from all animals treated with clinically relevant doses of zoledronic acid. There was no evidence of a mineralising defect, no aberrant accumulation of osteoid, and no woven bone in treated animals.
CLINICAL STUDIES: Clinical trial results for the treatment of postmenopausal osteoporosis: Core study (HORIZON-PFT): In a randomized, double-blind, placebo-control trial, Aclasta significantly decreased the risk of one or more new/worsening vertebral fractures at 1 year (58%), 2 years (68%) and 3 years (67%) (all p<0.0001) and also the risk of at least one new moderate or severe vertebral fracture at 1 year (60%), 2 years (71%) and 3 years (70%) (all p<0.0001). Aclasta treatment also reduced the risk of hip fracture by 40% over 3 years (p=0.003). Furthermore, Aclasta treatment had beneficial effects on all clinical fractures, bone mineral density, bone histology, bone turnover markers, height, and disability.
Extension study: In a three year extension study in which subjects initially treated with three infusions of Aclasta were randomized to placebo or Aclasta treatment, three additional annual Aclasta infusions compared to placebo significantly (p<0.05) reduced the risk of new morphometric vertebral fracture (3.0% vs. 6.2%) and new/worsening morphometric vertebral fracture (3.4% vs. 7.0%).
Clinical trial results in the prevention of clinical fractures after hip fracture: In male and female patients with a recent low-trauma hip fracture, treatment with Aclasta significantly reduced the incidence of any clinical fracture by 35%; 46% reduction in the risk of a clinical vertebral fracture, 27% reduction in the risk for non-vertebral fractures and also 30% reduced risk for a subsequent hip fracture. Aclasta treatment significantly increased BMD relative to placebo at the hip and femoral neck (12, 24, and 36 month time points).
Clinical trial results for the treatment of male osteoporosis (MO): In one randomized active-control study an annual infusion of Aclasta was similar to weekly alendronate for the percentage change in lumbar spine BMD at month 12 and non-inferior at month 24 relative to baseline. In a second randomized, placebo-control study Aclasta significantly reduced the risk of new morphometric vertebral fracture by 63% and was superior to placebo in increasing or preserving BMD at the lumbar spine, total hip, and femoral neck over 24 months (all, p < 0.05).
Clinical trial results in the treatment and prevention of glucocorticoid-induced osteoporosis: In a randomized, active-control trial in patients with glucocorticoid-induced osteoporosis, increases in BMD were significantly greater in the Aclasta treated group at all sites, which included the lumbar spine, femoral neck, total hip, trochanter, and distal radius at 12 months compared to risedronate 5 mg daily (all p <0.03).
Clinical trial results for the prevention of postmenopausal osteoporosis: In a randomized, double-blind, placebo-control trial in women with postmenopausal osteoporosis, Aclasta significantly increased lumbar spine BMD relative to placebo at month 24. Aclasta administered annually for two years or as a single dose both significantly increased total hip BMD relative to placebo at month 24 (all p <0.0001).
Paget's disease of bone: In two 6-month randomized comparative, well-controlled clinical trials, in patients with Paget's disease, Aclasta demonstrated a superior and more rapid response in serum alkaline phosphatase compared with risedronate. In addition, more Aclasta-treated patients demonstrated normalization bone turnover as reflected in biochemical markers of bone formation and resorption compared with risedronate treated patients.
Pharmacokinetics: Single and multiple 5 and 15-minute infusions of 2, 4, 8 and 16 mg zoledronic acid in 64 cancer patients with bone metastases yielded the following pharmacokinetic data, which were found to be dose independent. Pharmacokinetic data in patients with osteoporosis and Paget's disease of bone are not available.
After initiation of the zoledronic acid infusion, plasma concentrations of the active substance increased rapidly, achieving their peak at the end of the infusion period, followed by a rapid decline to <10% of peak after 4 hours and <1% of peak after 24 hours, with a subsequent prolonged period of very low concentrations not exceeding 0.1% of peak levels.
Intravenously administered zoledronic acid is eliminated by a triphasic process: rapid biphasic disappearance from the systemic circulation, with half-lives of t_½alpha 0.24 and t_½beta 1.87 hours, followed by a long elimination phase with a terminal elimination half-life of t_½gamma 146 hours. There was no accumulation of the active substance in plasma after multiple doses given every 28 days. The early disposition phases (alpha and beta, with t_½ values as previously mentioned) presumably represent rapid uptake into bone and excretion via the kidneys.
Zoledronic acid is not metabolised and is excreted unchanged via the kidney. Over the first 24 hours, 39 ± 16% of the administered dose is recovered in the urine, while the remainder is principally bound to bone tissue. From the bone tissue it is released very slowly back into the systemic circulation and eliminated via the kidney. The total body clearance is 5.04 ± 2.5 L/h, independent of dose, and unaffected by gender, age, race or body weight. The inter- and intra-subject variation for plasma clearance of zoledronic acid was shown to be 36% and 34%, respectively. Increasing the infusion time from 5 to 15 minutes caused a 30% decrease in zoledronic acid concentration at the end of the infusion, but had no effect on the area under the plasma concentration versus time curve.
Drug-drug interactions: No specific drug-drug interaction studies have been conducted with zoledronic acid. Since zoledronic acid is not metabolised in humans and the substance was found to have little or no capacity as a direct-acting and/or irreversible metabolism-dependent inhibitor of P450 enzymes, zoledronic acid is unlikely to reduce the metabolic clearance of substances which are metabolised via the cytochrome P450 enzyme systems. Zoledronic acid is not highly bound to plasma proteins (approximately 23 to 40% bound) and binding is concentration independent. Therefore, interactions resulting from displacement of highly protein-bound drugs are unlikely.
Special populations (see DOSAGE & ADMINISTRATION): Renal impairment: The renal clearance of zoledronic acid was correlated with creatinine clearance, renal clearance representing 75 ± 33% of the creatinine clearance, which showed a mean of 84 ± 29 mL/min (range 22 to 143 mL/min) in the 64 patients studied. Small observed increases in AUC_(0-24hr), by about 30% to 40% in mild to moderate renal impairment, compared to a patient with normal renal function, and lack of accumulation of drug with multiple doses irrespective of renal function, suggest that dose adjustments of zoledronic acid in mild (Cl_cr= 50 to 80 mL/min) and moderate (Cl_cr= 30 to 50 mL/min) renal impairment are not necessary. The use of Aclasta in patients with creatinine clearance <35 mL/min is contraindicated due to an increased risk of renal failure in this population (see CONTRAINDICATIONS). No dose adjustment is necessary in patients with creatinine clearance ≥35 mL/min.
Toxicology: NON-CLINICAL SAFETY DATA: Toxicity Studies: In the bolus parenteral studies, zoledronic acid was well tolerated when administered subcutaneously to rats and intravenously to dogs at doses of up to 0.02 mg/kg daily for 4 weeks. Administration of 0.001 mg/kg/day subcutaneously in rats and 0.005 mg/kg intravenously once every 2 to 3 days in dogs for up to 52 weeks was also well tolerated.
The kidney was identified as a target organ for toxicity in parenteral studies with zoledronic acid. In intravenous infusion studies, renal tolerability was observed in rats at doses of up to 0.6 mg/kg and in dogs up to 0.5 mg/kg but dosing intervals were different.
The most frequent finding in the repeat-dose studies consisted of increased primary spongiosa in the metaphyses of long bones in growing animals at nearly all doses, a finding that reflected the compound's pharmacological antiresorptive activity.
Reproductive toxicity: For reproductive toxicity see USE IN PREGNANCY & LACTATION.
Mutagenicity: Zoledronic acid was not mutagenic in vitro and in vivo in the mutagenicity tests performed.
Carcinogenicity: In oral carcinogenicity studies in rodents, zoledronic acid revealed no carcinogenic potential.