Denosumab

Osteoporosis and Bone Loss

Denosumab is used to treat osteoporosis in individuals who are at a high risk for bone fractures. This includes:

• Women who have gone through menopause.
• Men with osteoporosis.
• Men and women who are taking corticosteroid medications (such as prednisone) for a long period of time.

It is also used to prevent bone loss and increase bone mass in people receiving certain cancer treatments that can weaken bones, specifically:

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

Cancer-Related Bone Conditions

This medication is also used to manage specific bone issues related to cancer or its complications, including:

• Preventing fractures, spinal cord compression, or the need for radiation or surgery in people with multiple myeloma or solid tumors that have spread to the bone (bone metastases).
• Treating giant cell tumor of bone in adults and some adolescents when the tumor cannot be safely removed by surgery.
• Lowering high blood calcium levels caused by cancer (hypercalcemia of malignancy) when the condition has not responded to other treatments like bisphosphonates.

How Denosumab Works

Bone is a living tissue that is constantly being broken down and replaced. In a healthy body, there is a balance between the cells that build bone and the cells that dissolve it. Denosumab works by targeting the specific process that leads to bone loss.

The medication is a monoclonal antibody designed to recognize and bind to a protein called RANK ligand. This protein is essential for the formation, function, and survival of osteoclasts, which are the cells that break down bone. By binding to this protein, denosumab prevents it from activating the osteoclasts.

When the activity of these bone-dissolving cells is reduced, the following effects occur:

• Bone breakdown is slowed down.
• Bone mass and density are increased.
• Bones become stronger and less likely to break or fracture.

In cases where cancer has spread to the bones, this process also helps to limit bone destruction and reduce the risk of complications like fractures or bone pain.

Common Side Effects

• Back pain or pain in the arms and legs
• Muscle or joint pain
• Fatigue or headache
• Nausea, diarrhea, or constipation
• Skin irritation, such as redness, itching, or dryness
• Symptoms of a cold or upper respiratory infection

Serious Side Effects

• Low blood calcium (hypocalcemia): Symptoms include muscle spasms, twitches, cramps, or numbness and tingling in the fingers, toes, or around the mouth.
• Jaw bone problems: Pain, swelling, or sores in the mouth or jaw that do not heal.
• Unusual bone fractures: New or unusual pain in the hip, groin, or thigh.
• Serious skin infections: Red, swollen, tender, or warm skin, sometimes accompanied by fever.
• Severe allergic reactions: Rash, hives, swelling of the face or throat, and difficulty breathing.
• Severe bone, joint, or muscle pain: Intense pain that may develop days, months, or years after starting treatment.

Boxed Warning: Severe Hypocalcemia

Denosumab can cause severely low blood calcium levels (hypocalcemia), which may lead to hospitalization or life-threatening events. This risk is significantly higher for individuals with advanced chronic kidney disease, particularly those on dialysis or those with mineral and bone metabolism disorders. Symptoms of low calcium may include muscle spasms, twitches, numbness, tingling, or seizures.

Bone and Jaw Concerns

• Osteonecrosis of the Jaw: This medication is associated with a risk of jaw bone decay (osteonecrosis). This condition often occurs after invasive dental procedures, such as tooth extractions, or in patients with poor oral hygiene.
• Atypical Femoral Fractures: Some patients have experienced unusual fractures of the thigh bone with little or no trauma. These may be preceded by new or unusual pain in the hip, groin, or thigh.
• Vertebral Fractures after Discontinuation: When treatment is stopped, the risk of multiple fractures in the spine (vertebrae) increases. Healthcare providers typically recommend transitioning to a different bone-strengthening therapy if denosumab is discontinued.

Infections and Skin Reactions

Denosumab may increase the risk of serious infections, including those of the skin, urinary tract, and ears. Patients may also develop dermatologic conditions such as dermatitis, eczema, or rashes. Any signs of infection, such as fever, chills, or skin that is red, swollen, or tender to the touch, require medical evaluation.

Hypersensitivity and Pregnancy

• Allergic Reactions: Serious hypersensitivity reactions, including anaphylaxis, facial swelling, and hives, have been reported.
• Pregnancy: This medication can cause harm to a developing fetus. It is generally not recommended for use during pregnancy, and effective contraception is typically advised during treatment and for several months after the last dose.

Pregnancy

Denosumab may cause harm to an unborn baby and is generally not recommended for use during pregnancy. Healthcare providers typically advise individuals who can become pregnant to use effective birth control methods during treatment and for at least 5 months after the last dose. If you become pregnant while using this medication, you should contact your doctor immediately to discuss the potential risks.

Breastfeeding

It is not known whether denosumab passes into human breast milk. Because of the potential for serious side effects in a nursing infant, healthcare providers usually recommend either discontinuing breastfeeding or stopping the medication. The decision depends on the medical necessity of the drug for the mother. Consult with a healthcare professional to weigh the benefits and risks before breastfeeding while using this medication.

Available Forms

Denosumab is available as a clear, colorless to pale yellow liquid solution. It is designed for subcutaneous injection, which means it is injected into the fatty tissue just beneath the skin. It is typically supplied in the following formats:

• Single-dose prefilled syringes: These are used for specific treatment schedules, often administered once every six months.
• Single-dose vials: These are used for dosing schedules that may occur more frequently, such as every four weeks.

Strengths

The medication comes in different concentrations depending on the condition being treated. Common strengths include:

• 60 milligrams (mg) per 1 milliliter (mL) of solution.
• 120 milligrams (mg) per 1.7 milliliters (mL) of solution.

Because the dosage and frequency depend on the specific medical reason for the treatment, denosumab is usually administered by a healthcare provider in a clinical setting.

FDA Approval and Indications

The U.S. Food and Drug Administration (FDA) has approved denosumab for several specific uses, including:

• Treatment of osteoporosis in postmenopausal women and in men at high risk for bone fracture.
• Treatment of bone loss in patients receiving certain treatments for prostate or breast cancer.
• Treatment of giant cell tumor of bone that cannot be removed by surgery or where surgery is likely to cause severe morbidity.
• Treatment of high calcium levels caused by cancer (hypercalcemia of malignancy) when other treatments have not worked.

Boxed Warning

In early 2024, the FDA added a Boxed Warning—its most serious safety notification—to the prescribing information for certain denosumab products. This warning highlights an increased risk of severe hypocalcemia (dangerously low blood calcium levels) in patients with advanced chronic kidney disease, particularly those on dialysis or those with a condition called mineral and bone disorder.

Severe hypocalcemia can lead to serious complications, including hospitalization, seizures, or death. The FDA requires healthcare providers to screen patients for kidney disease before starting the medication and to monitor calcium levels closely in those at high risk.

Biosimilar Status

The FDA has approved biosimilar versions of denosumab. These medications are highly similar to and have no clinically meaningful differences from the original biological product in terms of safety, purity, and potency.

Factors Influencing Cost

The total price of denosumab treatment is determined by several variables, including the specific brand prescribed and the patient's insurance plan. Because this medication is an injection administered by a healthcare professional, costs typically include both the drug and the clinical service fee for the office visit.

Insurance and Assistance

Coverage for denosumab is common under most major insurance plans, including Medicare, as it is usually administered in a doctor's office or outpatient clinic. For patients facing high out-of-pocket costs, support may be available through:

• Co-pay Assistance: Programs for eligible patients with commercial insurance to help reduce out-of-pocket expenses.
• Patient Assistance Programs: Programs offered by manufacturers for those without insurance or who meet specific financial criteria.

Biosimilar Options

The FDA has approved biosimilar versions of denosumab. These products are highly similar to the original reference drugs and may offer a more affordable treatment option depending on insurance formulary preferences and pharmacy benefit designs.