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General Information

Prolia (denosumab) is a fully human monoclonal antibody that specifically binds to and inhibits the receptor activator of NF-kappaB ligand (RANK Ligand), the primary mediator of bone resorption. RANK Ligand is the protein responsible for activating osteoclasts, the cells that break down bone. An increased amount of the protein has been linked as the primary cause of a broad range of bone loss conditions including osteoporosis, treatment-induced bone loss, bone erosions in rheumatoid arthritis (RA), and bone metastases.

Prolia is specifically indicated for the following patients at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture:

• Postmenopausal women with osteoporosis at high risk for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy.

• To increase bone mass in men with osteoporosis at high risk for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy.

• Glucocorticoid-induced osteoporosis in men and women at high risk of fracture who are either initiating or continuing systemic glucocorticoids in a daily dosage equivalent to 7.5mg or greater of prednisone and expected to remain on glucocorticoids for at least 6months.

• To increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for non-metastatic prostate cancer.

• To increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer.

Prolia is supplied as a solution for subcutaneous administration. The recommended initial dose is 60 mg administered as a single subcutaneous injection once every 6 months. Prolia should be administered via subcutaneous injection in the upper arm, the upper thigh, or the abdomen.

Clinical Results

FDA Approval

The FDA approval of Prolia for the treatment of postmenopausal osteoporosis was based on a 3-year, randomized, double-blind, placebo-controlled trial. The trial enrolled 7,808 women aged 60 to 91 years with a baseline BMD T-score between -2.5 and -4.0 at either the lumbar spine or total hip. Women with other diseases or on therapy that affect bone were excluded. The women were randomized to receive SC injections of either placebo or Prolia 60 mg once every 6 months. All women received at least 1000 mg calcium and 400 IU vitamin D supplementation daily. The primary efficacy endpoint was the incidence of new morphometric (radiologically-diagnosed) vertebral fractures at 3 years. Prolia significantly reduced the incidence of new morphometric vertebral fractures at 1, 2, and 3 years. The incidence of new vertebral fractures at year 3 was 7.2% in the placebo-treated women compared to 2.3% for the Prolia-treated women.

The FDA approval of Prolia to increase bone mass in men with osteoporosis was based on a 1-year, randomized, double-blind, placebo-controlled trial. Enrolled men (n=242) had a baseline BMD T-score between -2.0 and -3.5 at the lumbar spine or femoral neck. Men with a BMD T-score between -1.0 and -3.5 at the lumbar spine or femoral neck were also enrolled if there was a history of prior fragility fracture. The subjects were randomized to receive SC injections of either placebo (n=121) or Prolia 60mg (n =121) once every 6 months. All men received at least 1000mg calcium and at least 800IU vitamin D supplementation daily. The primary efficacy variable was percent change in lumbar spine Bone Mineral Density (BMD) from baseline to 1-year. The treatment differences in BMD at 1-year were 4.8% (+0.9% placebo, +5.7% Prolia; at the lumbar spine, 2.0% (+0.3% placebo, +2.4% Prolia) at the total hip, and 2.2% (0.0% placebo, +2.1% Prolia) at femoral neck.

The FDA approval of Prolia in the treatment of patients with glucocorticoid-induced osteoporosis was based on the 12-month primary analysis of a 2-year, randomized, multicenter, double-blind, parallel-group, active-controlled study of 795 patients (70% women and 30% men) aged 20 to 94 years (mean age of 63 years) treated with greater than or equal to 7.5mg/day oral prednisone (or equivalent) for < 3 months prior to study enrollment and planning to continue treatment for a total of at least 6 months (glucocorticoid-initiating subpopulation; n = 290) or ≥ 3 months prior to study enrollment and planning to continue treatment for a total of at least 6 months (glucocorticoid-continuing subpopulation, n = 505). Enrolled patients <50 years of age were required to have a history of osteoporotic fracture. Patients were randomized (1:1) to receive either an oral daily bisphosphonate (active-control, risedronate 5mg once daily) (n = 397) or Prolia 60mg subcutaneously once every 6 months (n = 398) for one year. Patients received at least 1000mg calcium and 800IU vitamin D supplementation daily. In the glucocorticoid-initiating subpopulation, Prolia significantly increased lumbar spine BMD compared to the active-control at one year (Active-control 0.8%, Prolia 3.8%) with a treatment difference of 2.9%. In the glucocorticoid-continuing subpopulation, Prolia significantly increased lumbar spine BMD compared to active-control at one year (Active-control 2.3%, Prolia 4.4%) with a treatment difference of 2.2%.

The FDA approval of Prolia in the treatment of bone loss in men with non-metastatic prostate cancer receiving androgen deprivation therapy (ADT) was based on a 3-year, randomized (1:1), double-blind, placebo-controlled, multi-national study conducted in 1,468 men. The mean baseline lumbar spine BMD T-score was -0.4, and 22% of men had a vertebral fracture at baseline. Men were randomized to receive subcutaneous injections of either placebo (n=734) or Prolia 60mg (n=734) once every 6 months for a total of 6 doses. Randomization was stratified by age (<70 years vs. ≥70 years) and duration of ADT at trial entry (≤6 months vs. >6 months). Seventy-nine percent of patients received ADT for more than 6months at study entry. All men received at least 1000mg calcium and 400IU vitamin D supplementation daily. The primary efficacy variable was percent change in lumbar spine BMD from baseline to month 24. Lumbar spine BMD was higher at 2 years in Prolia-treated patients as compared to placebo-treated patients [-1.0% placebo, +5.6% Prolia; treatment difference 6.7%].

The FDA approval of Prolia for the treatment of bone loss in women receiving adjuvant aromatase inhibitor (AI) therapy for breast cancer was based on a 2-year, randomized (1:1), double-blind, placebo-controlled, multinational study. Women (n=252) had baseline BMD T-scores between -1.0 to-2.5 at the lumbar spine, total hip, or femoral neck, and had not experienced fracture after age 25. The mean baseline lumbar spine BMD T-score was -1.1,and 2.0% of women had a vertebral fracture at baseline. Women were randomized to receive subcutaneous injections of either placebo (n=125) or Prolia 60mg (n=127) once every 6 months for a total of 4 doses. Randomization was stratified by duration of adjuvant AI therapy at trial entry (≤6months vs. >6months). Sixty-two percent of patients received adjuvant AI therapy for more than 6 months at study entry. All women received at least 1000mg calcium and 400IU vitamin D supplementation daily. The primary efficacy variable was percent change in lumbar spine BMD from baseline to month 12. Lumbar spine BMD was higher at 12 months in Prolia-treated patients as compared to placebo-treated patients [-0.7% placebo, +4.8% Prolia; treatment difference 5.5%].

Side Effects

Adverse events associated with the use of Prolia for postmenopausal osteoporosis may include, but are not limited to, the following:

Back pain

Pain in extremity

Hypercholesterolemia

Musculoskeletal pain

Cystitis

Pancreatitis

Adverse events associated with the use of Prolia for male osteoporosis may include, but are not limited to, the following:

back pain

arthralgia

nasopharyngitis 

Adverse events associated with the use of Prolia for glucocorticoid-induced osteoporosis may include, but are not limited to, the following:

back pain

hypertension

bronchitis

headache

Adverse events associated with the use of Prolia for bone loss due to hormone ablation for cancer may include, but are not limited to, the following:

arthralgia

back pain

pain in extremity

musculoskeletal pain

Mechanism of Action

Prolia (denosumab) is a fully human monoclonal antibody that binds to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. Prolia 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.

Literature References

Brown JP, Prince RL, Deal C, Recker RR, Kiel DP, de Gregorio LH, Hadji P, Hofbauer LC, Alvaro-Gracia JM, Wang H, Austin M, Wagman RB, Newmark R, Libanati C, San Martin J, Bone HG Comparison of the Effect of Denosumab and Alendronate on Bone Mineral Density and Biochemical Markers of Bone Turnover in Postmenopausal Women With Low Bone Mass: A Randomized, Blinded, Phase 3 Trial. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2009 Dec 14:1-34

Lewiecki EM, Miller PD, McClung MR, Cohen SB, Bolognese MA, Liu Y, Wang A, Siddhanti S, Fitzpatrick LA; AMG 162 Bone Loss Study Group Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2007 Dec;22(12):1832-41