Denosumab is a RANK ligand (RANKL) inhibitor indicated for: Treatment of postmenopausal women with osteoporosis at high risk for fracture
Mechanism of action:
Denosumab binds to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. Denosumab prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone.
Pharmacodynamics:
In clinical studies, treatment with 60 mg of Denosumab resulted in reduction in the bone resorption marker serum type 1 C-telopeptide (CTX) by approximately 85% by 3 days, with maximal reductions occurring by 1 month. At the end of each dosing interval, CTX reductions were partially attenuated from a maximal reduction of ≥ 87% to ≥ 45% (range: 45% to 80%), as serum Denosumab levels diminished, reflecting the reversibility of the effects of Denosumab on bone remodeling. These effects were sustained with continued treatment. Upon reinitiating, the degree of inhibition of CTX by Denosumab was similar to that observed in patients initiating Denosumab treatment.
Consistent with the physiological coupling of bone formation and resorption in skeletal remodeling, subsequent reductions in bone formation markers (i.e., osteocalcin and procollagen type 1 N-terminal peptide [PlNP]) were observed starting 1 month after the first dose of Denosumab. After discontinuation of Denosumab therapy, markers of bone resorption increased to levels 40-60% above pretreatment values but returned to baseline levels within 12 months.
Pharmacokinetics
In a study conducted in healthy male and female volunteers (n = 73, age range: 18 to 64 years) following a single subcutaneously administered Denosumab dose of 60 mg after fasting (at least for 12 hours), The median time to maximum Denosumab concentration (Tmax) was 10 days (range: 3 to 21 days). After Cmax, serum Denosumab concentrations declined over a period of 4 to 5 months with a mean half-life of 25.4 days (SD = 8.5 days; n=46). The mean area-under-the-concentration-time curve up to 16 weeks (AUC0-16 weeks) of Denosumab was 316 mcg⋅day/mL (SD = 101 mcg⋅day/mL).
No accumulation or change in Denosumab pharmacokinetics with time was observed upon multiple dosing of 60 mg subcutaneously administered once every 6 months. Denosumab pharmacokinetics was not affected by the formation of binding antibodies. A population pharmacokinetic analysis was performed to evaluate the effects of demographic characteristics. This analysis showed no notable differences in pharmacokinetics with age (in postmenopausal women), race, or body weight (36 to 140 kg).
Drug Interactions
No drug-drug interaction studies have been conducted
DOSAGE AND ADMINISTRATION:
– Administer 60 mg every 6 months as a subcutaneous injection in the upper arm, upper thigh, or abdomen
– Instruct patients to take calcium 1000 mg daily and at least 400 IU vitamin D daily
CONTRAINDICATIONS
• Hypocalcemia
Warnings and Precautions:
– Hypocalcemia: Must be corrected before initiating Denosumab as this may worsen especially in patients with renal impairment. Adequately supplement patients with calcium and vitamin D
– Serious infections including skin infections: May occur, including those leading to hospitalization. Advise patients to seek prompt medical attention if they develop signs or symptoms of infection, including cellulitis
– Dermatologic reactions: Dermatitis, rashes, and eczema have been reported. Consider discontinuing Denosumab if severe symptoms develop
– Osteonecrosis of the jaw: Has been reported with Denosumab. Monitor for symptoms
– Suppression of bone turnover: Significant suppression has been demonstrated. Monitor for consequences of bone over suppression which may result in significant suppression of bone remodeling as evidenced by markers of bone turnover and bone histomorphometry