Denosumab

Usage

Denosumab is prescribed for the treatment of osteoporosis in postmenopausal women at high risk of fracture, and in men at high risk of fracture receiving androgen deprivation therapy (ADT) for non-metastatic prostate cancer. It is also used to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer, and to treat bone loss associated with long-term systemic glucocorticoid therapy. It is also prescribed for the treatment of giant cell tumor of bone (GCTB) and hypercalcemia of malignancy refractory to bisphosphonate therapy.

Denosumab’s pharmacological classification is RANK ligand (RANKL) inhibitor.

Denosumab works by binding to and inhibiting RANKL, a protein essential for the formation, function, and survival of osteoclasts (cells that break down bone). By inhibiting RANKL, denosumab decreases bone resorption and increases bone density, thus reducing the risk of fractures.

Alternate Names

Denosumab is marketed under the brand names Prolia® (60 mg dose for osteoporosis) and Xgeva® (120 mg dose for cancer treatment).

How It Works

Pharmacodynamics: Denosumab binds to RANKL, mimicking the action of osteoprotegerin (OPG), a natural inhibitor of RANKL. This inhibits the maturation, activation, and survival of osteoclasts, thereby reducing bone resorption. The reduction in bone resorption leads to increased bone mineral density and decreased fracture risk.

Pharmacokinetics: Denosumab is administered subcutaneously and reaches peak serum concentrations in approximately 10 days. It has a half-life of approximately 26 days and is eliminated through binding to RANKL and subsequent receptor-mediated clearance. No dose adjustment is needed for patients with renal or hepatic impairment.

Mode of Action: Denosumab’s mode of action involves receptor binding to RANKL, preventing its interaction with the RANK receptor on osteoclasts. This inhibition disrupts the signaling pathway necessary for osteoclast formation, function, and survival.

Elimination Pathways: Denosumab is eliminated through binding to RANKL followed by receptor-mediated clearance. Since it does not undergo hepatic metabolism, no dose adjustment is required for hepatic impairment. It is not significantly excreted by the kidneys.

Dosage

Standard Dosage

Adults:

• Osteoporosis (Prolia®): 60 mg subcutaneously every 6 months.
• Cancer Treatment (Xgeva®): 120 mg subcutaneously every 4 weeks (some regimens may adjust dosing frequency based on individual response and tolerance).
• Giant Cell Tumor of Bone: 120 mg subcutaneously every 4 weeks with additional 120 mg doses on days 8 and 15 of the first month of treatment.
• Glucocorticoid-induced Osteoporosis: 60 mg subcutaneously every 6 months.

Children:

Denosumab is generally not recommended for pediatric use, except for adolescents with giant cell tumor of bone where the dosage is 120mg subcutaneously every 4 weeks, with additional doses on days 8 and 15 of the first month. Pediatric safety and efficacy have not been fully established for other conditions.

Special Cases:

• Elderly Patients: No dose adjustment is necessary.
• Patients with Renal Impairment: No dose adjustment is necessary. Monitor calcium levels closely, particularly in patients with severe renal impairment or on dialysis.
• Patients with Hepatic Dysfunction: No dose adjustment is necessary.
• Patients with Comorbid Conditions: Careful monitoring and dose adjustments may be necessary for patients with certain conditions, such as diabetes, cardiovascular disease, or those receiving immunosuppressants.

Clinical Use Cases

Denosumab is not typically used in clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its primary use is in chronic conditions like osteoporosis, treatment of bone complications in certain cancers, and GCTB.

Dosage Adjustments

Dosage adjustments are generally not required based on renal or hepatic function. However, calcium and Vitamin D supplementation is crucial, especially in patients with renal impairment. Dose adjustments may be considered based on patient response and tolerance, especially in oncology settings.

Side Effects

Common Side Effects:

• Back pain
• Musculoskeletal pain
• Skin reactions (e.g., eczema, dermatitis, rash)
• Upper respiratory tract infections
• Urinary tract infections
• Constipation
• Elevated cholesterol levels

Rare but Serious Side Effects:

• Hypocalcemia (low blood calcium levels)
• Osteonecrosis of the jaw (ONJ)
• Atypical femoral fractures
• Serious infections (e.g., cellulitis)
• Severe allergic reactions

Long-Term Effects:

Long-term effects may include increased risk of ONJ and atypical femoral fractures with continued use. Rapid bone loss can occur upon discontinuation, increasing the risk of multiple vertebral fractures.

Adverse Drug Reactions (ADR):

• Hypocalcemia (can manifest as muscle spasms, tetany, seizures)
• ONJ (jaw pain, swelling, loosening of teeth)
• Atypical femoral fracture (thigh or groin pain)
• Severe allergic reactions (anaphylaxis)

Contraindications

• Hypocalcemia
• Hypersensitivity to denosumab
• Pregnancy

Drug Interactions

• Immunosuppressants (increased risk of infection): Patients on denosumab should be monitored for infection.
• Etelcalcetide (increased risk of hypocalcemia): Co-administration should be avoided.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Denosumab is contraindicated in pregnancy. It can cross the placenta and may cause fetal harm. A negative pregnancy test is required before starting treatment, and effective contraception should be used during treatment and for 5 months after the last dose.

• Breastfeeding: It is unknown if denosumab is excreted in breast milk. Due to the potential for adverse effects in the infant, breastfeeding is not recommended while taking denosumab.

Drug Profile Summary

• Mechanism of Action: RANKL inhibitor, reducing bone resorption by inhibiting osteoclast formation, function, and survival.
• Side Effects: Common: Back pain, musculoskeletal pain, skin reactions, infections, constipation. Serious: Hypocalcemia, ONJ, atypical femoral fractures, serious infections.
• Contraindications: Hypocalcemia, hypersensitivity, pregnancy.
• Drug Interactions: Immunosuppressants (increased infection risk), Etelcalcetide (increased hypocalcemia risk).
• Pregnancy & Breastfeeding: Contraindicated in pregnancy; breastfeeding not recommended.
• Dosage: Osteoporosis: 60 mg SC every 6 months; Cancer: 120 mg SC every 4 weeks (adjustments possible); GCTB: 120 mg SC every 4 weeks + loading doses.
• Monitoring Parameters: Serum calcium, creatinine, vitamin D, signs of infection, dental health (for ONJ), and thigh/groin pain (for atypical femoral fractures).

Popular Combinations

Denosumab is often used in combination with calcium and vitamin D supplementation to mitigate the risk of hypocalcemia.

Precautions

• General Precautions: Monitor calcium, vitamin D, and renal function. Dental examination prior to starting therapy is recommended. Assess for risk factors for ONJ.
• Specific Populations: Contraindicated in pregnancy. Breastfeeding not recommended. Close monitoring of calcium levels in children and elderly.
• Lifestyle Considerations: Maintain good oral hygiene. Report any new thigh or groin pain.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Denosumab?

A: Prolia (osteoporosis): 60mg SC every 6 months. Xgeva (cancer): 120 mg SC every 4 weeks (dosing adjustments possible). Pediatric (GCTB): 120 mg SC every 4 weeks, loading doses days 8 and 15 of first month.

Q2: What is the mechanism of action of Denosumab?

A: Denosumab is a RANKL inhibitor that binds to and inhibits RANKL, preventing it from interacting with RANK receptors on osteoclasts. This inhibition reduces osteoclast formation, function, and survival, leading to decreased bone resorption and increased bone density.

Q3: What are the serious side effects of Denosumab?

A: Serious side effects include hypocalcemia, osteonecrosis of the jaw (ONJ), atypical femoral fractures, and serious infections.

Q4: What are the contraindications for using Denosumab?

A: Denosumab is contraindicated in patients with pre-existing hypocalcemia and hypersensitivity to denosumab. It’s also contraindicated during pregnancy.

Q5: What are the important drug interactions with Denosumab?

A: Co-administration with immunosuppressants may increase the risk of infection. The risk of hypocalcemia increases when denosumab is combined with Etelcalcetide.

Q6: Can Denosumab be used during pregnancy or breastfeeding?

A: Denosumab is contraindicated during pregnancy. Breastfeeding is not recommended while taking denosumab.

Q7: What monitoring is required for patients on Denosumab?

A: Monitor serum calcium, vitamin D, renal function, dental health, and watch for signs of infection, thigh/groin pain.

Q8: What should be done if a patient develops hypocalcemia while on Denosumab?

A: Hypocalcemia should be corrected before initiating Denosumab therapy. Calcium and vitamin D supplementation is crucial. If hypocalcemia occurs during treatment, it must be managed promptly with additional calcium and vitamin D.

Q9: What is the significance of a dental examination prior to Denosumab initiation?

A: A dental examination helps identify any pre-existing dental conditions or risk factors for osteonecrosis of the jaw (ONJ), which can inform treatment decisions and management strategies. Any necessary dental procedures should ideally be completed before starting denosumab.

Q10: What is the recommended course of action upon discontinuation of Denosumab?

A: Due to the rapid bone loss that can occur after discontinuation, transitioning to another antiresorptive therapy (e.g., bisphosphonate) is essential to mitigate the risk of fractures.