Denosumab - Uses, Dosage, Side Effects, Drug Warnings, and Precautions

Overview:

Denosumab is a human monoclonal antibody that is used in the treatment of osteoporosis, giant cell tumors of bone, bone metastasis, and treatment-induced bone loss. It is a RANKL (receptor activator of nuclear factor kappa-B ligand) inhibitor that inhibits the development of osteoclasts (cells responsible for bone breakdown). It was developed by Amgen biotechnology company.

Denosumab was approved by the United States Food and Drug Administration (FDA) on June 2, 2010, for use in postmenopausal women with osteoporosis. It is the first FDA-approved RANKL inhibitor. It was approved for use in bone metastasis to prevent skeletal-related events in November 2010. FDA approved Denosumab on June 13, 2013, for use in the treatment of giant cell tumors of bone that cannot be surgically resected or where resection could result in morbidity. In Europe, the committee for medicinal products for human use (CHMP) issued a positive opinion on Denosumab on December 17, 2009, for treating osteoporosis in postmenopausal women and bone loss in men who are under hormone ablation therapy for prostate cancer. The European Commission approved the marketing of Denosumab on May 28, 2010.

How Does Denosumab Work?

The bone remodeling process progressively removes old bone tissue and replaces it with new bone with the help of osteoblasts (cells that form bone), osteoclasts (cells that resorb bone), and osteocytes (bone cells). The pre-osteoclast (precursors to osteoclasts) cells express a surface receptor RANK (receptor activator of nuclear factor-kappa B), which is a member of the TNFR (tumor necrosis factor receptor) superfamily. RANKL exists as cell surface molecules on osteoblasts and activates RANKL. This activation stimulates the maturation of pre-osteoclasts into osteoclasts.

Denosumab binds to RANKL and inhibits it to prevent the maturation of osteoclasts. It mimics the action of osteoprotegerin, an endogenous RANKL inhibitor that is present in reduced concentrations in patients with osteoporosis. This inhibition by Denosumab prevents bone degradation and the progression of the disease.

Uses:

• Denosumab is used to treat giant cell tumors of bone that are unresectable or if surgical resection is unlikely.

• It is used in the treatment of osteoporosis in postmenopausal women and men who are at high risk for fracture. In addition, it is used if other therapies for osteoporosis are unsuccessful.

• Denosumab is used in the treatment of glucocorticoid-induced osteoporosis.

• It is used to increase bone mass in men receiving androgen deprivation therapy for prostate cancer that is nonmetastatic, as they are at high risk for fracture.

• It is used to increase bone mass in women receiving aromatase inhibitor therapy as adjuvant therapy for breast cancer, as they are at high risk for fracture.

• Denosumab is used in patients with multiple myeloma and bone metastases from solid tumors to prevent skeletal-related events.

• It is used to treat bisphosphonate-refractory hypercalcemia associated with malignancy.

Dosage:

Denosumab is an injectable solution that is available in doses of 60 mg/mL and 120 mg/1.7 mL. For the treatment of giant cell tumors of bone in adults and skeletally mature adolescents, 120 mg of Denosumab is administered subcutaneously once every four weeks during the first month of treatment. A 120 mg dose is also given on day eight and day 15.

Warnings:

Denosumab is commercially available under two different names, labeled by FDA for different indications. These two products should not be used concomitantly.

• Pregnancy: Denosumab may harm the fetus. According to clinical studies, it may cause fetal loss, postnatal mortality, stillbirths, absent lymph nodes, reduced bone strength, abnormal bone growth, dental dysplasia, reduced hematopoiesis, and reduced neonatal growth. Hence, Denosumab should not be used in pregnant women. A pregnancy test should be done prior to Denosumab therapy.

• Hypersensitivity: Denosumab should not be used if allergic reactions like anaphylaxis, hypotension, dyspnea, swelling of lips, face, or throat, hypotension, and breathing difficulty occur.

• Latex Sensitivity: Some prefilled syringes contain latex in the form of dry natural rubber. It should not be handled by individuals allergic to latex.

• Hypocalcemia and Mineral Metabolism: Denosumab may decrease serum calcium concentrations and can exacerbate pre-existing hypocalcemia. Hence, it should be used only after correcting the pre-existing hypocalcemia.

• Infections: It may increase the risk of infections. Serious infections like cellulitis, erysipelas, infections of the abdomen, urinary tract, and ear, and endocarditis were reported.

• Dermatologic Reactions: It causes dermatological reactions like dermatitis, eczema, and rashes.

• Musculoskeletal Pain: Denosumab can cause bone, joint, and/or muscle pain in some patients.

• Suppression of Bone Turnover: It causes a significant reduction in bone formation and bone turnover rates. However, the long-term effects of bone modeling suppression associated with Denosumab remain unknown.

For Patients:

What Is Giant Cell Bone Tumor?

A giant cell tumor of the bone is a rare benign tumor of the bone that has the potential for aggressive behavior. It undergoes metastases in one to nine percent of cases. The giant cell tumor is characterized by the presence of osteoclast-like cells (multinucleated giant cells). It is commonly found at the ends of long bones around the growth plate, extending into the epiphysis and the joint surface. It affects the metaphysis and the epiphysis of the long bones. It occurs in young adults after the completion of skeletal bone growth. It is common in adults between 20 and 40 years of age and usually affects the distal femur and proximal tibia; distal radius; proximal humerus; sacrum; and the vertebral bodies.

What Causes Giant Cell Bone Tumor?

The giant cell tumors are thought to result from overexpression of RANK or RANKL by neoplastic mononuclear stromal cells with hyperproliferation of osteoclasts. The giant cell tumors associated with pheochromocytoma-paraganglioma and giant cell tumor syndrome are due to early H3.3 mutation. However, the exact cause responsible for the giant cell tumors has not been identified.

What Happens in Giant Cell Bone Tumors?

The giant cell tumor causes pain and limits the range of motion due to the proximity of the tumor to the joint space. The tumor progressively grows and causes swelling. It causes symptoms like muscle aches, pain in arms or legs, and abdominal pain. It also causes nerve pain. The giant cell tumor causes complications, including pathological fractures, tumor recurrence, lung metastases, and compression of nerve roots in proximity to the tumor.

Learn More About Denosumab

Facts to Know Before Starting Denosumab:

When and Why Switch to Denosumab?

The giant cell tumor of bone is a benign tumor with aggressive potential. It causes aggressive bone resorption. The tumor requires surgical resection. Various chemotherapeutic agents are used to treat this tumor. Medications like glucocorticoids and bisphosphonates are used to prevent bone loss. Denosumab is used instead of bisphosphonates because it binds to RANKL and inhibits the differentiation of osteoclasts. It has a greater antiresorptive effect compared to bisphosphonates.

How Effective Is Denosumab?

Denosumab has a greater antiresorptive effect, and it slows down the rate of resorption. It effectively reduces osteoclast-mediated bone resorption and blocks the protein and suppresses the cells responsible for the breakdown of bone. It strengthens the bone and also reduces the risk of pathological fractures. It also improves bone density by slowing down bone loss.

Things to Inform the Doctor Before Denosumab Is Prescribed

1. The presence of allergic reactions to Denosumab or any other medications should be informed.

2. There are no relevant studies to determine the risk of Denosumab use in pregnant and breastfeeding women. It may harm the unborn baby. Pregnancy and breastfeeding should be informed to the doctor.

3. Denosumab interacts with certain drugs. If the patient is taking medications for any other condition, they should be informed.

4. The presence of any other known medical conditions should be informed to the doctor before starting Denosumab.

5. Denosumab lowers the calcium in the blood. Hence, the presence of hypocalcemia should be informed before starting Denosumab.

Starting Denosumab:

How to Take Denosumab?

Denosumab is not available for oral use. It is an injectable drug that is administered subcutaneously (under the skin). It is not available for intramuscular, intravenous, or intradermal use. Denosumab is administered subcutaneously by a doctor or healthcare professional. It is usually given as a shot under the skin of the upper arm, upper thigh, or stomach. In the first month, 120 mg of Denosumab is given subcutaneously on days 1, 8, and 15. Then, 120 mg of Denosumab is given subcutaneously every four weeks as a maintenance dose.

Things to Follow While Under Denosumab:

1. Patients should carefully read the US (United States) FDA-approved patient labeling (medication guide).

2. Patients should know the importance of maintaining adequate calcium levels during the treatment. Calcium and vitamin D supplements should be properly taken if advised.

3. Patients should seek medical help if allergic reactions, dermatological reactions, bone pain, muscle pain, joint pain, or infection occurs during the course of the treatment.

4. Women of childbearing age should use effective birth control methods to prevent pregnancy during the course of therapy and for at least five months after taking the last dose.

5. Patients should maintain good oral hygiene during the therapy and should consult the dentist if problems like loose teeth, pain, or non-healing sores occur while under Denosumab.

Advice for Caregivers:

The caregivers should inform the doctor if the patient develops symptoms of allergic reactions like rashes, hives, and breathing difficulties; dermatological reactions like eczema and dermatitis; musculoskeletal pain, bone pain, and swelling.

Things to Do After Taking Denosumab:

It is important to inform the doctor if any noticeable symptoms are present after taking Denosumab. Any signs of allergic reactions, dermatological reactions, muscle pain, bone pain, or dental problems like jaw pain or tooth mobility should be informed to the doctor.

Diet Modifications:

Diet modifications are not necessary unless recommended by the doctor. A healthy and balanced diet can be followed. The use of alcohol or tobacco is not recommended during the course of the treatment.

Look Out for the Side Effects:

The patients should familiarize themselves with the common and rare side effects of Denosumab so that the symptoms can be easily recognized. If side effects are present, the treatment is modified accordingly. Denosumab may cause some other side effects that are not listed here. The common side effects include the following:

• Back pain.

• Irritation, blistering, itching, or reddening of the skin.

• Cracked, dry, or scaly skin.

• Rashes.

• Bloody or cloudy urine.

• Difficult or painful urination.

• Frequent urination.

• Muscle or bone pain.

• Pain in the arms or legs.

• Swelling.

Less common side effects are:

• Fever.

• Headache.

• Joint pain.

• Arm or jaw pain.

• Chest tightness or heaviness.

• Chills.

• Confusion.

• Congestion.

• Ear congestion.

• Muscle cramps.

• Muscle stiffness.

• Tremor.

• Difficulty swallowing.

• Difficulty breathing.

• Blood in the stools.

Staying on Denosumab:

Tips to Stay on Track:

The improvement in the symptoms of giant cell bone tumors after taking Denosumab can be experienced during the course of the treatment. If any side effects occur after taking Denosumab, it is essential to inform the doctor. Denosumab should be given on a fixed schedule. Appointments should not be skipped without the knowledge of the doctor.

Things to remember,

• It is important to stick to the dosage schedule of Denosumab because missing an appointment will affect the treatment outcome.

• It is essential to follow up regularly with the doctor, and improvement in symptoms should be informed.

For Doctors

Indications:

Denosumab is used for treating giant cell tumors of bone; osteoporosis in postmenopausal women and men; glucocorticoid-induced osteoporosis; bone loss associated with androgen deprivation therapy and aromatase inhibitor therapy; multiple myeloma and metastases of bone tumors; and hypercalcemia associated with malignancy.

Mechanism of Action:

The bone remodeling process progressively removes old bone tissue and replaces it with new bone with the help of osteoblasts (cells that form bone), osteoclasts (cells that resorb bone), and osteocytes (bone cells). The pre-osteoclast (precursors to osteoclasts) cells express a surface receptor RANK (receptor activator of nuclear factor-kappa B), which is a member of the TNFR (tumor necrosis factor receptor) superfamily. RANKL exists as cell surface molecules on osteoblasts and activates RANKL. RANKL mediates the maturation of pre-osteoclasts into osteoclasts.

Denosumab binds to RANKL (a protein essential for the formation of osteoclasts) and inhibits it to prevent the maturation of osteoclasts. It mimics the action of osteoprotegerin, an endogenous RANKL inhibitor that is present in reduced concentrations in patients with osteoporosis. This inhibition by Denosumab prevents bone degradation and the progression of the disease.

Pharmacodynamics:

Clinical studies showed that treatment with 60 mg of Denosumab caused a reduction in the bone resorption type 1 C-telopeptide by 85 percent in three days, with a maximal reduction in 1 month. Consistent reduction in bone formation markers (osteocalcin and procollagen type 1 N-terminal peptide) was noted starting one month after the first dose. After discontinuation of treatment, markers of bone resorption increased by 40 to 60 percent above the values before treatment, but it returned to baseline values within 12 months.

Pharmacokinetics:

Absorption

Denosumab has a long absorption phase. It takes ten days to reach peak serum concentration after a single subcutaneous dose of 60 mg of Denosumab. A reduction in bone resorption biomarkers was observed within three days, and maximal reduction was observed in 1 month. The bone resorption markers and bone mineral density levels returned to baseline value within 12 months after discontinuing the treatment.

Distribution

The distribution of Denosumab in human milk is not known. It is present in relatively low concentrations in seminal fluid (maximum concentration is approximately 2 percent of serum concentrations). However, the maximum concentration delivered to a female partner during intercourse is 11,000 times lower than the dose that the patient is receiving.

Metabolism and Elimination

Denosumab is a monoclonal antibody that is cleared by the reticuloendothelial system. The renal filtration and excretion are minimal, with an elimination half-life of 32 days and the terminal half-life is five to ten days.

Warnings and Precautions:

Denosumab is commercially available under two different names, labeled by FDA for different indications. Therefore, these two products should not be used concomitantly.

• Pregnancy: Denosumab may harm the fetus. According to clinical studies, it may cause fetal loss, postnatal mortality, stillbirths, absent lymph nodes, reduced bone strength, abnormal bone growth, dental dysplasia, reduced hematopoiesis, and reduced neonatal growth. Hence, Denosumab should not be used in pregnant women. A pregnancy test should be done prior to Denosumab therapy.

• Hypersensitivity: Denosumab should not be used if allergic reactions like anaphylaxis, hypotension, dyspnea, swelling of lips, face, or throat, hypotension, and breathing difficulty occur.

• Latex Sensitivity: Some prefilled syringes contain latex in the form of dry natural rubber. It should not be handled by individuals allergic to latex.

• Hypocalcemia and Mineral Metabolism: Denosumab may decrease serum calcium concentrations and can exacerbate pre-existing hypocalcemia. Hence, it should be used only after correcting the pre-existing hypocalcemia.

• Infections: It may increase the risk of infections. Serious infections like cellulitis, erysipelas, infections of the abdomen, urinary tract, and ear, and endocarditis were reported.

• Dermatologic Reactions: It causes dermatological reactions like dermatitis, eczema, and rashes.

• Musculoskeletal Pain: Denosumab can cause bone, joint, and/or muscle pain in some patients.

• Suppression of Bone Turnover: It causes a significant reduction in bone formation and bone turnover rates. However, the long-term effects of bone modeling suppression associated with Denosumab remain unknown.

• Osteonecrosis of the Jaw: Osteonecrosis of the jaw can occur in patients receiving Denosumab. It can occur spontaneously or due to tooth extraction and/or delayed healing.

• Atypical Subtrochanteric and Diaphyseal Femoral Fractures:These fracturesare reported in patients receiving Denosumab. Multiple vertebral fractures are also reported after discontinuing Denosumab.

• Hypercalcemia:This conditionis reported after the discontinuation of Denosumab therapy.

Indications and Uses:

• Denosumab is used in the treatment of giant cell tumors of bone that are unresectable or if surgical resection is unlikely.

• It is used in the treatment of osteoporosis in postmenopausal women and men who are at high risk for fracture. It is used if other therapies for osteoporosis are unsuccessful.

• Denosumab is used in the treatment of glucocorticoid-induced osteoporosis.

• It is used to increase bone mass in men receiving androgen deprivation therapy for prostate cancer that is nonmetastatic, as they are at high risk for fracture.

• It is used to increase bone mass in women receiving aromatase inhibitor therapy as adjuvant therapy for breast cancer, as they are at high risk for fracture.

• Denosumab is used in patients with multiple myeloma and bone metastases from solid tumors to prevent skeletal-related events.

• It is used to treat bisphosphonate-refractory hypercalcemia associated with malignancy.

Dosage Strength and Forms:

Denosumab is an injectable solution that is available in doses of 60 mg/mL and 120 mg/1.7 mL. For the treatment of giant cell tumors of bone in adults and skeletally mature adolescents, 120 mg of Denosumab is administered subcutaneously. It is usually given as a shot under the skin of the upper arm, upper thigh, or stomach. In the first month, 120 mg of Denosumab is given subcutaneously on days 1, 8, and 15. Then, 120 mg of Denosumab is given subcutaneously every four weeks as a maintenance dose.

Considerations for Administration:

• The pre-existing hypocalcemia should be corrected before starting Denosumab.

• One gram of calcium and at least 400 units of vitamin D should be given daily to patients receiving Denosumab for osteoporosis or bone loss associated with androgen deprivation or aromatase inhibitor therapy.

• Calcium, vitamin D, and magnesium supplements are essential for patients receiving Denosumab for giant cell tumors of bone.

Contraindication:

• Denosumab is contraindicated in patients with hypocalcemia.

• It is contraindicated in systemic hypersensitivity to Denosumab or other components of Denosumab.

• It is contraindicated in pregnant women.

Results from Clinical Trials:

A clinical study was performed to determine the safety and efficacy of Denosumab in patients with giant cell tumors. 686 patients were analyzed, of which 55 percent had giant cell tumors of bone, 45 percent had giant cell tumor recurrence, and 2 percent were experiencing secondary recurrence. The results showed that Denosumab effectively reduces tumor size by inhibiting osteoclastogenesis. However, it did not show any effect on recurrent tumors. Denosumab may be helpful in cases where tumor remnants are present after surgery. Also, the risk-benefit ratio should be considered before starting Denosumab.

Drug Interactions:

Interactions With Other Drugs:

Clinically important drug interactions have not been observed with the concomitant use of Denosumab with drugs metabolized by CYP3A4 (cytochrome enzyme). Some drugs may reduce serum calcium concentrations in patients receiving Denosumab.

Other Specifications:

• Pregnancy: Denosumab is contraindicated in pregnant women, as it may harm the fetus. It can cause stillbirth, fetal loss, and postnatal mortality.

• Breastfeeding: No information is available regarding the presence of Denosumab in human milk and its effects on breastfed infants.

• Pediatric use: The safety and efficacy of Denosumab in pediatric patients have not been established. Denosumab is not approved for pediatric use.

• Geriatric Use: A significant difference in responses to Denosumab between elderly and younger patients has not been identified.

• Renal Impairment: The renal filtration and excretion of Denosumab are very minimal. Hence, dose adjustment is not necessary for patients with renal impairment.

• Hepatic Impairment: No studies have been conducted to evaluate Denosumab in hepatic impairment patients.