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Prolia® mechanism of action

Prolia® (denosumab) targets RANKL on osteoclasts

Prolia® (denosumab) is a first in class therapy for postmenopausal women and men with osteoporosis and at increased risk of fracture. It is a monoclonal antibody that works by inhibiting RANKL in order to inhibit osteoclasts activity (formation, function, and survival) and decrease bone resorption.

Prolia® (denosumab) mechanism of action

Prolia® (denosumab) is a monoclonal antibody that binds with high affinity and specificity to the RANK ligand (RANKL). RANKL is an cytokine that acts as a key mediator of bone resorption. It normally binds to its receptor, RANK, found on the surface of osteoclast precursors and osteoclasts. By preventing the RANKL-RANK interaction, osteoclast activity such as formation, function, and survival are inhibited thereby preventing the breakdown of both cortical bone and trabecular bone. 

Prolia® (denosumab) is a medication for osteoporosis, and is the first antiresorptive therapy to target RANKL [25.3]. Earlier approved treatments for osteoporosis include bisphosphonates/biosphosphonate therapy, hormone replacement therapy (HRT), selective estrogen-receptor modulators; the parathyroid hormone analogue teriparatide that has an anabolic effect on bone tissue, and strontium ranelate that increases bone formation and decreases bone resorption. 

Prolia® (denosumab) is a medication for osteoporosis, and is the first antiresorptive therapy to target RANKL. 

Molecular details of Prolia® (denosumab) 

Denosumab is a human monoclonal antibody of the IgG2 subclass

Prolia® (denosumab) pharmacodynamics

Prolia® (denosumab) treatment reduces the rate of bone turnover, reaching a nadir for the bone resorption marker serum type 1 C-telopeptides (CTX) (85% reduction) by 3 days, with reductions maintained over the dosing interval.

At the end of each dosing interval, CTX reductions have been observed to be partially attenuated from maximal reduction of ≥ 87% to approximately ≥ 45% (range 45-80%), reflecting the reversibility of effects on bone remodeling once serum levels diminish. These effects were sustained with continued treatment.

In an interaction study, Prolia® (denosumab) did not affect the pharmacokinetics of midazolam, which is metabolized by cytochrome P450 3A4 (CYP3A4). This indicates that Prolia® (denosumab) should not alter the pharmacokinetics of drugs metabolized by CYP3A4.
Patients being treated with Prolia
® (denosumab) should not be treated concomitantly with other denosumab-containing medicinal products. 

Prolia® (denosumab) pharmacokinetics

Prolia® (denosumab) is composed solely of amino acids and carbohydrates. Its metabolism and elimination follow immunoglobulin clearance pathways, resulting in degradation to small peptides and individual amino acids. After Cmax, serum levels decline with a half-life of 26 days (range 6-52 days) over a period of 3 months (range 1.5-4.5 months). 

No accumulation or change in Prolia® (denosumab) pharmacokinetics with time has been observed upon subcutaneous multiple-dosing. Prolia® (denosumab) pharmacokinetics is not affected by the formation of binding antibodies and is similar in men and women. Age and race do not appear to significantly affect the pharmacokinetics of Prolia® (denosumab). In dose ranging studies, Prolia® (denosumab) exhibited non-linear, dose-dependent pharmacokinetics, with lower clearance at higher doses or concentrations, but approximately dose-proportional increases in exposures for doses of 60 mg and greater [27.4]. Prolia® (denosumab) is not expected to alter the pharmacokinetics of drugs metabolized by cytochrome P450 3A4 (CYP3A4).

Renal impairment

A study has shown that in patients with renal impairment, the degree of renal impairment has no effect on the pharmacokinetics of Prolia® (denosumab).

Hepatic impairment

No studies have been performed in patients with hepatic impairment, but since monoclonal antibodies are not eliminated via hepatic metabolic mechanisms, the pharmacokinetics of denosumab is not expected to be affected by hepatic impairment.

Pediatric population

The pharmacokinetic profile in pediatric populations has not been assessed.