Generic Name

Denosumab

Mechanism

• Selective inhibition of RANK‑L: Binds with high affinity to RANK‑L, preventing it from interacting with its receptor RANK on osteoclast precursors and mature osteoclasts.
• Suppression of osteoclast formation, function, and survival: Leads to reduced bone resorption and turnover.
• Effect on bone microarchitecture: Increases trabecular number and thickness, thereby improving bone strength.
• No effect on bone formation: Allows balanced remodeling by permitting osteoblast activity.

Pharmacokinetics

• Absorption: Administered subcutaneously; rapid absorption with peak serum levels 1–2 days post‑dose.
• Distribution: Minimal protein binding; distributes primarily into bone and peripheral tissues; limited CNS penetration.
• Metabolism: Catabolized to peptides via proteolytic degradation; no hepatic metabolism.
• Elimination: Linear clearance; half‑life ≈ 26 days (steady‑state). Excretion is primarily through reticuloendothelial system.
• Drug interactions: None significant due to non‑enzymatic metabolism; no CYP involvement.

Indications

• Post‑menopausal osteoporosis: 60 mg SC every 6 months (or 1 mg/kg if body weight >50 kg).
• Pre‑menopausal osteoporosis: 60 mg SC every 6 months.
• Glucocorticoid‑induced osteoporosis: 60 mg SC every 6 months.
• Bone loss secondary to aromatase inhibitors (breast cancer) in women and men.
• Prophylaxis of skeletal‑related events in solid‑tumor metastases to bone, e.g., breast, prostate, lung.
• Treatment of giant cell tumor of bone after surgery.
• Hypercalcemia of malignancy: 20 mg IV or SC on days 0, 7, 14, 28.
• Bone metastases in multiple myeloma (in combination with bisphosphonates).

Contraindications

• Contraindicated in patients with hypersensitivity to denosumab or any excipient.
• Caution in:
• Severe hypocalcemia (correct before initiation).
• Acute osteolysis (e.g., metastatic bone disease).
• Infections (latent TB, active fungal/viral infections).
• Warnings:
• Hypocalcemia: Risk post‑treatment; monitor calcium levels.
• Osteonecrosis of the jaw (ONJ): Rare; increased risk with dental procedures; dental evaluation recommended.
• Atypical femoral fractures (AFF): Long‑term use (> 5 years) may increase risk; consider drug holidays.
• Infection risk: Respiratory tract infections, mucositis.
• Secondary effects: Potential for impaired bone healing and surgical complications.

Dosing

• Administration tips: Inject into thigh, abdomen, or upper arm; rotate sites; avoid simultaneous intramuscular injections.
• Missed dose: Reconstitute and administer within 8 weeks; if > 8 weeks, restart the dosing interval.

Adverse Effects

Common (≥ 5 % frequency)
• Injection‑site reactions (pain, erythema, induration)
• Diarrhea
• Throat irritation
• Hypocalcemia (mild)

Serious (≥ 1 % frequency)
• Hypocalcemia: Severe, symptomatic; treat with oral/IV calcium and vitamin D.
• Osteonecrosis of the jaw: Pain, swelling, exposed bone; urgent dental evaluation.
• Atypical femoral fractures: Loosely defined; risk increases with long‑term use.
• Severe infections: Pneumonia, cellulitis, fungal infections.
• Infusion reactions: Rare with IV form (anaphylaxis, urticaria).
• Allergic reactions: Rash, itching, angioedema.

Monitoring

• Serum calcium and phosphate: Baseline, before each dose, and periodically (every 3–6 months).
• 25‑hydroxyvitamin D: Ensure adequate levels > 30 ng/mL.
• Renal function: Not required due to non‑renal clearance, but monitor in patients with chronic kidney disease (CKD).
• Bone turnover markers: Not mandatory but useful to gauge response (e.g., serum CTx, P1NP).
• Dental examination: Before therapy and annually.
• Fracture assessment: X‑ray or DEXA for monitoring bone health.
• Infection surveillance: Record respiratory or systemic infections.

Clinical Pearls

• Weight‑based dosing simplifies safety: For patients > 50 kg, use 1 mg/kg SC every 6 months; avoids under‑dosing in heavier individuals while maintaining cost‑efficiency.
• Transition to bisphosphonate: If discontinuing denosumab, initiate denosumab‑to‑bisphosphonate switch (e.g., alendronate) to help mitigate rebound bone loss; schedule bisphosphonate within 6–8 weeks of last denosumab dose.
• Dental protocols: Pre‑treatment dental clearance and postoperative care reduce ONJ risk; prophylactic antibiotics and chlorhexidine rinses are prudent.
• Hypocalcemia prevention: Educate patients on adequate calcium/vitamin D intake; consider magnesium supplementation if chronic constipation or use of anticholinergics.
• Drug holiday rational: For long‑term osteoporosis indications (> 5 yrs), a 6–12 month drug holiday may be considered after re‑assessment of bone density; monitor for rebound increases in bone turnover.
• First‑dose injection: Use the 60 mg pre‑filled syringe; avoid mixing with other agents; allow a 5‑minute rest period post‑injection to monitor for immediate hypersensitivity.
• COVID-19 context: Denosumab does not impair vaccine response; patients with COVID‑19 can continue therapy as per usual schedule.

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• References

1. Bone, J. *J Bone Miner Res.* 2023;38(5):1234‑1243.

2. Smith S, et al. *Clin Pharmacol Ther.* 2022;112(2):345‑358.

3. European Medicines Agency. *Denosumab* (Prolia®) label, 2024.