Introduction
Prolia (denosumab) is a fully human monoclonal antibody that specifically targets receptor activator of nuclear factor kappa-B ligand (RANKL), a key mediator of osteoclast formation, function, and survival. Developed by Amgen, it represents a novel approach to bone metabolism modulation and is classified as a RANK ligand inhibitor. Prolia was first approved by the FDA in 2010 for the treatment of postmenopausal women with osteoporosis at high risk for fracture.
Mechanism of Action
Prolia exerts its therapeutic effects by binding with high affinity and specificity to RANKL, a cytokine essential for the formation, function, and survival of osteoclasts. By inhibiting RANKL, denosumab prevents osteoclast-mediated bone resorption, thereby reducing bone turnover and increasing bone mineral density. Unlike bisphosphonates, which are incorporated into bone matrix, Prolia acts on the RANKL pathway extracellularly without being incorporated into bone, allowing for reversible inhibition of bone resorption.
Indications
FDA-approved indications include:
- Treatment of postmenopausal women with osteoporosis at high risk for fracture
- Increase bone mass in men with osteoporosis at high risk for fracture
- Treatment of glucocorticoid-induced osteoporosis in men and women at high risk of fracture
- Treatment to increase bone mass in men receiving androgen deprivation therapy for nonmetastatic prostate cancer at high risk for fracture
- Treatment to increase bone mass in women receiving adjuvant aromatase inhibitor therapy for breast cancer at high risk for fracture
Dosage and Administration
- Standard dosage: 60 mg administered subcutaneously every 6 months
- Administration: Subcutaneous injection in the upper arm, upper thigh, or abdomen
- Special populations: No dosage adjustment required for renal impairment (including patients on dialysis) or hepatic impairment
- Important: Patients must receive adequate calcium and vitamin D supplementation
Pharmacokinetics
- Absorption: Bioavailability is 64% following subcutaneous administration
- Distribution: Apparent volume of distribution is 3.28 L; does not bind to blood cells
- Metabolism: Expected to be degraded via proteolytic enzymes throughout the body
- Elimination: Elimination half-life is approximately 25.4 days; cleared by the reticuloendothelial system
- No known metabolic pathways involving cytochrome P450 enzymes
Contraindications
- Hypersensitivity to denosumab or any component of the formulation
- Pre-existing hypocalcemia (must be corrected prior to initiation)
- Pregnancy (category D: based on animal studies showing fetal harm)
Warnings and Precautions
- Hypocalcemia: May occur, especially in patients with renal impairment; correct hypocalcemia before initiation
- Atypical femoral fractures: Have been reported; evaluate patients with thigh or groin pain
- Osteonecrosis of the jaw: May occur; perform preventive dental exam before treatment
- Serious infections: Increased risk of serious infections may occur
- Dermatological reactions: Including eczema, dermatitis, and rashes
- Multiple vertebral fractures: Have been reported after discontinuation
Drug Interactions
- No formal drug interaction studies conducted
- Theoretical interactions with immunosuppressants may increase infection risk
- Calcium supplements and vitamin D should be administered as needed
- Use caution with other drugs that lower calcium levels
Adverse Effects
Common adverse reactions (≥5%):- Back pain (34.7%)
- Pain in extremity (11.7%)
- Musculoskeletal pain (7.6%)
- Hypercholesterolemia (7.2%)
- Cystitis (5.9%)
- Hypocalcemia
- Serious infections
- Dermatological reactions
- Atypical femoral fractures
- Osteonecrosis of the jaw
Monitoring Parameters
- Serum calcium levels prior to each dose and within 14 days after initiation
- Bone mineral density (BMD) assessment every 1-2 years
- Renal function tests
- Dental examinations before initiation and periodically during treatment
- Monitor for signs and symptoms of infection
- Assessment for thigh or groin pain (atypical fracture screening)
- Vitamin D levels periodically
Patient Education
- Importance of calcium and vitamin D supplementation
- Need for regular dental check-ups and good oral hygiene
- Recognition of symptoms of low calcium (muscle spasms, twitching, numbness)
- Report any thigh or groin pain immediately
- Inform all healthcare providers about Prolia treatment
- Do not stop treatment without discussing with healthcare provider
- Understanding that treatment is administered every 6 months
References
1. Cummings SR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756-765. 2. FDA Prescribing Information: Prolia (denosumab). Amgen Inc. 2021. 3. Bone HG, et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM extension trial. Osteoporos Int. 2020;31(8):1451-1464. 4. Watts NB, et al. Insights from the denosumab clinical trial program. J Bone Miner Res. 2012;27(11):2169-2173. 5. McClung MR, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354(8):821-831. 6. Miller PD, et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone. 2008;43(2):222-229.