What is Prolia (Denosumab)?
Prolia (denosumab) is a fully human monoclonal antibody that binds to RANKL (receptor activator of nuclear factor kappa-B ligand), preventing osteoclast formation and bone resorption, administered as a 60 mg subcutaneous injection every 6 months for the treatment of osteoporosis and prevention of skeletal-related events. 1
Mechanism of Action
Denosumab works by binding to RANKL, a protein essential for osteoclast formation, function, and survival 1. By preventing RANKL from activating its receptor (RANK) on osteoclast surfaces, denosumab inhibits bone resorption and increases bone mass and strength in both cortical and trabecular bone 1. This results in approximately 85% reduction in bone resorption markers within 3 days of administration, with maximal reductions occurring by 1 month 1.
FDA-Approved Indications
Prolia is approved for multiple clinical scenarios 1:
- Postmenopausal osteoporosis in women at high risk for fracture who cannot use or have failed other osteoporosis medications 1
- Osteoporosis in men at high risk for fracture 1
- Glucocorticoid-induced osteoporosis in men and women taking corticosteroids (such as prednisone) for at least 6 months 1
- Bone loss prevention in men receiving androgen deprivation therapy for non-metastatic prostate cancer 1
- Bone loss prevention in women receiving aromatase inhibitor therapy for non-metastatic breast cancer 1
- Giant cell tumor of bone (GCTB) when surgery is not possible or unacceptably morbid, and in patients with metastases 2
Clinical Efficacy
In the landmark FREEDOM trial of 7,868 postmenopausal women with osteoporosis, denosumab demonstrated superior fracture reduction over 3 years 3:
- 68% relative reduction in vertebral fractures (2.3% vs 7.2% with placebo) 3
- 40% relative reduction in hip fractures (0.7% vs 1.2% with placebo) 3
- 20% relative reduction in nonvertebral fractures (6.5% vs 8.0% with placebo) 3
Denosumab shows greater bone mineral density increases compared to bisphosphonates, with 3.5% increase at the hip versus 2.6% for alendronate at 12 months 2, 4.
Administration and Dosing
Prolia is administered as a 60 mg subcutaneous injection once every 6 months 1. For giant cell tumor of bone, the dosing regimen includes three loading doses at weekly intervals, followed by monthly injections 2.
All patients require daily calcium and vitamin D supplementation during treatment 2, 1. Adequate contraception is mandatory in women of childbearing potential, as pregnancy must be avoided during treatment and for at least 5 months after the last dose 1.
Critical Safety Warnings
Hypocalcemia
Low blood calcium is a serious risk, particularly in patients with chronic kidney disease (eGFR < 30 mL/min/1.73 m²) 1. Severe hypocalcemia resulting in hospitalization and fatal cases have been reported postmarketing 1. Calcium and vitamin D supplementation is essential before and during treatment 1.
Osteonecrosis of the Jaw (ONJ)
Severe jaw bone problems may occur, with the most consistent risk factor being recent dental surgery or tooth extraction 1. Patients should have a dental examination before starting Prolia and practice good oral hygiene throughout treatment 1.
Atypical Femoral Fractures
Unusual thigh bone fractures can occur, presenting as new or unusual pain in the hip, groin, or thigh 1.
Rebound Vertebral Fractures
The most critical safety concern is the increased risk of multiple vertebral fractures after stopping, skipping, or delaying Prolia 1. This rebound effect occurs because bone resorption markers increase to 40-60% above pretreatment values upon discontinuation 1. If denosumab must be discontinued, bisphosphonate therapy must be initiated within 6 months to suppress rebound osteolysis 5.
Serious Infections
Denosumab may affect the body's ability to fight infections, with increased risk of skin infections, abdominal infections, bladder infections, ear infections, and endocarditis 1. Patients with weakened immune systems face higher infection risk 1.
Special Populations
Renal Impairment
No dose adjustment is necessary, but patients with advanced chronic kidney disease face greater risk of hypocalcemia 1. The American Society of Clinical Oncology recommends denosumab as preferred therapy in patients with creatinine clearance < 60 mL/min due to its efficacy in this population 5.
Giant Cell Tumor of Bone
In GCTB, denosumab achieved 86% tumor response rate with near-complete elimination of giant cells in evaluable patients 2. It is indicated when surgery is not possible or before surgery to solidify soft tissue components, facilitating resection 2. Treatment duration up to 6 months is reasonable for responding tumors, though inoperable tumors may require lifelong treatment 2.
Contraindications
Prolia is contraindicated in patients with 1:
- Hypocalcemia (low blood calcium levels)
- Pregnancy or planned pregnancy
- Allergy to denosumab or any ingredient in Prolia
Common Side Effects
The most common side effects in postmenopausal women include back pain, arm and leg pain, high cholesterol, muscle pain, and bladder infection 1. In men with osteoporosis, common effects are back pain, joint pain, and common cold symptoms 1.