What is Prolia (denosumab) used for in adults with a history of osteoporosis?

What is Prolia (Denosumab)?

Prolia (denosumab) is a fully human monoclonal antibody that inhibits RANKL (receptor activator of nuclear factor kappa-B ligand), thereby preventing osteoclast formation and reducing bone resorption, administered as 60 mg subcutaneously every 6 months for the treatment of osteoporosis. 1

Mechanism of Action

• Denosumab binds to and neutralizes RANKL, a key cytokine that regulates osteoclast differentiation, activity, and survival 2, 3
• By preventing RANKL from binding to its receptor on osteoclasts, denosumab decreases bone resorption and increases bone mineral density 4
• Unlike bisphosphonates, denosumab does not incorporate into bone matrix and its effects are rapidly reversible upon discontinuation 3

FDA-Approved Indications

Postmenopausal Osteoporosis:

• Treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as history of osteoporotic fracture, multiple risk factors, or failure/intolerance to other therapies) 1

Male Osteoporosis:

• Treatment to increase bone mass in men with osteoporosis at high risk for fracture 1

Glucocorticoid-Induced Osteoporosis:

• Treatment in men and women at high risk receiving ≥7.5 mg prednisone equivalent daily for at least 6 months 1

Cancer Treatment-Related Bone Loss:

• Men receiving androgen deprivation therapy for nonmetastatic prostate cancer 1
• Women receiving adjuvant aromatase inhibitor therapy for breast cancer 1

Clinical Efficacy

Fracture Reduction (FREEDOM Trial):

• Vertebral fractures reduced by 68% (2.3% vs 7.2% with placebo) 5
• Hip fractures reduced by 40% (0.7% vs 1.1% with placebo) 5
• Nonvertebral fractures reduced by 20% (6.1% vs 7.5% with placebo) 5

Long-Term Efficacy:

• Benefits sustained over up to 10 years of continuous treatment in extension studies 5, 6
• Continued BMD increases throughout treatment duration 6

Dosing and Administration

• Standard dose: 60 mg subcutaneous injection every 6 months 1
• Administration sites: Upper arm, upper thigh, or abdomen 1
• Required supplementation: Calcium 1000 mg daily and at least 400 IU vitamin D daily 1
• If a dose is missed, administer as soon as possible and resume 6-month schedule from that date 1

Position in Treatment Algorithm

The American College of Physicians recommends:

• Bisphosphonates as first-line therapy for primary osteoporosis 5
• Denosumab as second-line therapy for patients with contraindications to or adverse effects from bisphosphonates 5

Denosumab may be appropriate as initial therapy for:

• Patients with renal impairment (eGFR <60 mL/min) since it is not renally cleared 7
• Patients with gastrointestinal contraindications to oral bisphosphonates 4
• Older patients who have difficulty with oral bisphosphonate dosing requirements 8
• Patients previously treated with bisphosphonates who require additional therapy 5

Critical Safety Considerations

Pre-Treatment Requirements:

• Pregnancy testing mandatory in all females of reproductive potential before each dose 1
• Dental examination required before initiating therapy to minimize osteonecrosis of the jaw risk 5
• In patients with advanced chronic kidney disease (eGFR <30 mL/min), evaluate for CKD-MBD with iPTH, serum calcium, and vitamin D levels 1

Severe Hypocalcemia Warning:

• Patients with advanced chronic kidney disease are at greater risk of severe, potentially fatal hypocalcemia 1
• Treatment in these patients should be supervised by a provider with expertise in CKD-MBD management 1

Common Adverse Effects:

• Arthralgia, nasopharyngitis, headache, extremity pain, upper respiratory infection, constipation, urinary tract infection, rash 5
• Overall serious adverse event rate similar to placebo (23.8% vs 23.9%) 5

Rare but Serious Complications:

• Osteonecrosis of the jaw: Incidence 0.01-0.3% in osteoporosis patients; avoid invasive dental procedures during treatment 5, 3
• Atypical femoral fractures: Rare but reported; evaluate any new thigh, hip, or groin pain 3, 8

Critical Discontinuation Warning

Never discontinue denosumab without immediate transition to alternative antiresorptive therapy:

• Discontinuation causes rapid rebound in bone turnover markers within weeks 3
• Increased risk of multiple vertebral fractures after stopping denosumab 6, 3, 8
• Transition to high-dose bisphosphonate (zoledronic acid 5 mg) within 6 months of last denosumab dose is mandatory 7
• This rebound phenomenon is unique to denosumab and does not occur with bisphosphonates 7

Comparison to Bisphosphonates

Advantages:

• Greater BMD increases at all skeletal sites compared to alendronate 6
• No gastrointestinal side effects 4
• Safe in renal impairment (not renally cleared) 7
• Convenient dosing (twice yearly vs weekly/monthly oral or yearly IV) 2

Key Difference:

• Denosumab does not incorporate into bone matrix, so effects are rapidly reversible—drug holidays are contraindicated unlike with bisphosphonates 7, 3

Special Populations

Cancer-Related Bone Disease:

• Denosumab is effective in delaying skeletal-related events and bone pain in metastatic bone disease from solid tumors and myeloma 5
• For cancer patients, preventive dental measures are necessary before starting therapy 5

Breast Cancer Patients on Aromatase Inhibitors:

• Denosumab significantly reduces clinical fracture risk (HR 0.50) in the ABCSG-18 trial 5
• Reduces incident morphometric vertebral fractures regardless of baseline BMD 5

Prostate Cancer Patients on ADT:

• Increases lumbar spine BMD by 5.6% vs 1.0% loss with placebo 5
• Decreases new vertebral fractures at 36 months (1.5% vs 3.9%; RR 0.38) 5