Prolia (Generic name: Denosumab) is a monoclonal antibody that binds to the RANK ligand and inhibits the activation of osteoclasts. Thus, it inhibits bone loss and prevents & treats osteoporosis. It also inhibits giant cell bone tumors by inhibiting RANK activation.

It is a preferred drug for the treatment of osteoporosis and other conditions in patients with renal impairment. It has an onset of action of about 3 days with the maximal response seen in about a month. In patients with hypercalcemia of malignancy, it takes about 9 days to act and 23 days for a complete response.

When the treatment is discontinued, the markers of bone resorption return to baseline within 12 months. It has a bioavailability of about 62% and a half-life elimination of about 25 - 28 days. The time to reach the peak serum concentration is about 10 days (ranging from 3 - 21 days).

Denosumab Uses:

• Bone metastases from solid tumors (Xgeva):
  • Preventing bone-related complications in patients with cancer that has spread to the bones.
• Giant cell tumor of bone (Xgeva):
  • Treating a bone tumor (called a giant cell tumor) that cannot be removed through surgery or when surgery can cause serious complications, in adults and teenagers whose bones have fully developed.
• Glucocorticoid- induced osteoporosis (Prolia):
  • Treating bone thinning caused by taking steroid medications (glucocorticoids) in patients who are at high risk of breaking bones, and who are starting or continuing to take a daily dose of steroid equivalent to at least 7.5 mg of prednisone for at least 6 months.
  • High risk means the patient has had a bone fracture due to osteoporosis in the past, has multiple risk factors for fractures, or has not responded well to other treatments for osteoporosis or cannot tolerate them.
• Hypercalcemia of malignancy (Xgeva):
  • Treating high levels of calcium caused by cancer that are not responding to bisphosphonate therapy.
• Multiple myeloma (Xgeva):
  • Preventing bone-related complications in patients with multiple myeloma.
• Osteoporosis/bone loss (Prolia):
  • Treating bone thinning in postmenopausal women who are at high risk of fractures.
  • Treating bone thinning in men who are at high risk of fractures to increase bone mass.
  • Treating bone loss in men who are receiving androgen-deprivation therapy for nonmetastatic prostate cancer to increase bone mass.
  • Treating bone loss in women who are receiving aromatase inhibitor therapy for breast cancer to increase bone mass.
• Off Label Use of Denosumab in Adults:
  • Damage to bones due to rheumatoid arthritis.

Denosumab Dose in Adult

Note: Provide calcium and vitamin D supplements when needed to prevent or treat low levels of calcium in the blood (hypocalcemia).

Dose in the treatment of Bone metastases from solid tumors (prevention of skeletal-related events; Xgeva):  

• Inject 120 milligrams of the medication under the skin every 4 weeks,

Dose in the treatment of Giant cell tumor of bone (Xgeva):  

• Inject 120 milligrams of the medication under the skin once every 4 weeks.
• In the first month, also inject an additional 120 milligrams on days 8 and 15.

Dose in the treatment of Hypercalcemia of malignancy (Xgeva):  

• Inject 120 milligrams of the medication under the skin every 4 weeks.
• In the first month, also inject an additional 120 milligrams on days 8 and 15.

Dose in the treatment of Multiple myeloma (prevention of skeletal-related events; Xgeva):  

• Inject 120 milligrams of the medication under the skin every 4 weeks.
• It is important to note that denosumab has a reversible mechanism of action and should not be stopped suddenly, as recommended by ASCO (Anderson in 2018).

Dose in the treatment of Osteoporosis/bone loss (Prolia):

• Treatment of androgen deprivation-induced bone loss in men with prostate cancer:
  • Inject a single dose of 60 milligrams of the medication under the skin once every 6 months.
• Treatment of aromatase inhibitor-induced bone loss in women with breast cancer:
  • Inject a single dose of 60 milligrams of the medication under the skin once every 6 months.
• Treatment of glucocorticoid-induced osteoporosis:
  • Inject a single dose of 60 milligrams of the medication under the skin once every 6 months.
• Treatment of osteoporosis in men or in postmenopausal women:
  • Administer a single dose of 60 milligrams of the medication via subcutaneous injection once every 6 months.

• Discontinuation/interruption of therapy:  
  • When denosumab is stopped, BMD returns to its original level quickly, so it is not suggested to take a break from the drug.
  • Instead, if the use of denosumab is stopped, it is recommended to consider beginning an alternative osteoporosis treatment.

Dose in the treatment of Bone destruction caused by rheumatoid arthritis (off-label):  

Denosumab Dose in Children

Note: Administer calcium and vitamin D as necessary to prevent or treat hypocalcemia.

Dose in the treatment of Giant cell tumor of the bone: Xgeva:  

• Adolescents (skeletally mature) weighing ≥45 kg:
  • For adolescents who have matured skeletal structures and weigh at least 45 kg, the recommended dosage is a subcutaneous injection of 120 mg once every four weeks.
  • During the first month of treatment, an additional dose of 120 mg should be given on days 8 and 15.

Risks related to Pregnancy Denosumab (Prolia, Xgeva)

• Pregnant women should not use Prolia as it may harm the fetus based on animal studies and its mechanism of action.
• Women of childbearing age should confirm their pregnancy status before starting treatment and use effective contraception during treatment and for at least 5 months after the last dose.
• Denosumab, the active ingredient in Prolia, is a type of human antibody that may increase fetal exposure as pregnancy progresses.
• Studies show that low levels of denosumab are present in semen in men using it for osteoporosis treatment, but exposure from seminal fluid of men receiving higher doses is unknown, so their pregnant partners should be informed about the potential risk.

Denosumab use during breastfeeding:

• The presence of denosumab in breast milk is unknown.
• Women who are breastfeeding should consider the benefits of continuing denosumab treatment versus the potential risks to their infant.
• In animal studies, exposure to denosumab during pregnancy resulted in impaired mammary gland development and lactation postpartum, but this has not been fully studied in humans.
• Female offspring exposed to denosumab in utero had normal mammary gland histopathology at 6 months.

Dose in Kidney Disease:

Patients who have severe kidney impairment (creatinine clearance of less than 30 mL/minute) or who are on dialysis may have an increased risk of developing hypocalcemia (low calcium levels). Therefore, close monitoring of these patients is recommended.

Prolia:

• Denosumab does not require a dose adjustment in patients with renal impairment.
• It may be a good option for treating osteoporosis in patients with mild to moderate renal impairment (stage 1-3 CKD), although evidence in severe renal impairment (stage 4 CKD) is limited.
• However, it is not recommended for use in patients on dialysis or with end-stage renal disease (stage 5 CKD).
• Close monitoring is recommended for patients with severe renal impairment due to an increased risk of hypocalcaemia.

Xgeva:

• The manufacturer's labelling does not provide any recommendations for dosage adjustments.
• However, guidelines suggest that dosage adjustment is not necessary, but it is important to closely monitor patients for the risk of hypocalcaemia (ASCO [Anderson 2018]; ASCO/CCO [Van Poznak 2017]; Gravalos 2016).

Dose in Liver Disease:

Dosage adjustments have not been studied in liver disease and are not provided in the manufacturer's labeling.

Side Effects Caused by Denosumab (Prolia, Xgeva):

Percentages noted with Prolia (60 mg every 6 months) or Xgeva (120 mg every 4 weeks).

Common Side Effects of Denosumab Include:

• Cardiovascular:
  • Peripheral Edema
  • Hypertension
• Central Nervous System:
  • Fatigue
  • Headache
• Dermatologic:
  • Skin Rash
  • Dermatitis
  • Eczema
• Endocrine & Metabolic:
  • Hypophosphatemia
  • Hypocalcemia
• Gastrointestinal:
  • Diarrhea
  • Nausea
  • Decreased Appetite
  • Vomiting
  • Constipation
• Hematologic & Oncologic:
  • Anemia
  • Thrombocytopenia
• Neuromuscular & Skeletal:
  • Asthenia
  • Back Pain
  • Arthralgia
  • Limb Pain
• Respiratory:
  • Dyspnea
  • Cough
  • Upper Respiratory Tract Infection

Less Common Side Effects Of Denosumab Include:

• Cardiovascular:
  • Angina Pectoris
• Central Nervous System:
  • Sciatica
• Endocrine & Metabolic:
  • Hypercholesterolemia
  • Hypokalemia; Hypomagnesemia
  • Severe Hypocalcemia
• Gastrointestinal:
  • Upper Abdominal Pain
  • Flatulence
• Genitourinary:
  • Urinary Tract Infection
• Hematologic & Oncologic:
  • Malignant Neoplasm
• Infection:
  • Serious Infection
• Neuromuscular & Skeletal:
  • Musculoskeletal Pain
  • Ostealgia
  • Myalgia
  • Osteonecrosis Of The Jaw
  • Polymyalgia Rheumatic
• Ophthalmic:
  • Cataract
• Respiratory:
  • Pneumonia
  • Nasopharyngitis
  • Bronchitis

Contraindications to Denosumab Include:

Prolia:

Denosumab is contraindicated in patients with a known hypersensitivity to denosumab or any component of the formulation. It is also contraindicated in patients with preexisting hypocalcemia, and in pregnant women.

Xgeva:

Denosumab should not be used in patients with a known clinically significant hypersensitivity to denosumab or any component of the formulation. Additionally, denosumab should not be used in patients with preexisting hypocalcemia.

Warnings/Precautions

Bone fractures:

• Denosumab use has been associated with atypical femur fractures, which can occur without significant trauma and may be bilateral.
• Patients may experience pain in the hip, thigh, or groin before the fracture occurs. It is unclear if denosumab is the cause of these fractures as they can also occur in osteoporosis patients who are not treated with denosumab.
• Glucocorticoids may increase the risk of fractures. Patients should be advised to report any new or unusual pain in these areas and should be evaluated for an atypical or incomplete fracture if this occurs.
• Treatment with denosumab should be interrupted if an atypical femur fracture develops. After discontinuing denosumab, the risk of fractures increases particularly vertebral fractures.
• Patients with prior fractures or osteoporosis are at higher risk. The benefit and risk of denosumab treatment should be evaluated before initiation, especially in patients with prior vertebral fracture.
• If denosumab is discontinued, an alternative osteoporosis therapy should be considered, and post-denosumab bisphosphonate therapy may be recommended to mitigate bone mineral density decline.

Dermatologic reactions:

• Denosumab has been associated with dermatitis, eczema, and rash, which may not be specific to the injection site.
• If severe symptoms occur, consider discontinuing the medication.

Hypersensitivity:

• Denosumab has been associated with clinically significant hypersensitivity, including anaphylaxis.
• Patients may experience symptoms such as throat tightness, facial edema, upper airway edema, lip swelling, difficulty breathing, itching, rash, hives, and low blood pressure.
• If anaphylaxis or clinically significant hypersensitivity occurs, appropriate management should be initiated and denosumab should be permanently discontinued.

Hypercalcemia:

• Hypercalcemia (a high level of calcium in the blood that can cause various symptoms) can occur in patients with giant cell tumour of bone or in patients with growing skeletons several weeks to months after discontinuing denosumab therapy.
• It can lead to hospitalization and acute renal injury. Patients should be closely monitored for signs and symptoms of hypercalcemia, such as nausea, vomiting, headache, and decreased alertness, and serum calcium levels should be checked periodically.
• If hypercalcemia occurs, appropriate treatment should be initiated.

Hypocalcemia:

• Denosumab can cause low levels of calcium in the blood.
• This can be a serious problem, and some people have even died from it.
• People with kidney problems or who are on dialysis are more likely to have this problem.
• To help prevent this, doctors will check your calcium levels and correct any problems before starting treatment.
• Your doctor will also check your calcium levels more often if you are taking other medications that can lower calcium levels.
• People with certain medical conditions are more likely to have low calcium levels, so doctors will watch their calcium levels closely during treatment.
• Some people have had low calcium levels for weeks or months after treatment.
• If you have kidney problems, your levels of a hormone called parathyroid hormone may also go up.

Infection:

• Taking this medication may increase the chances of getting infections such as skin, stomach, urinary, ear, or gum infections.
• Rare cases of heart infection have also been reported.
• It is important to tell your doctor if you notice any signs of a serious infection, like redness or swelling on your skin.
• People who have a weak immune system or are taking other medicines that lower immunity may have a higher chance of getting a serious infection.
• Your doctor will decide if it is safe for you to keep taking this medicine if you get a serious infection.

Osteonecrosis of the jaw:

• Denosumab can cause a condition called Osteonecrosis of the Jaw (ONJ), which can lead to jaw pain, infections, and bone damage.
• Some factors that increase the risk of ONJ are invasive dental procedures, cancer, poor oral hygiene, and certain medications.
• To prevent ONJ, patients should have good oral hygiene and see a dentist before starting treatment.
• Cancer patients should avoid dental procedures while on denosumab, and patients who develop ONJ should see an oral surgeon.
• If ONJ occurs, the patient's doctor may consider stopping the use of denosumab.

Musculoskeletal pain:

• Sometimes people have severe pain in their bones, joints, or muscles when they take this medicine.
• It can happen right away or several months after starting the medicine.
• If this happens, the medicine may need to be stopped.

Breast cancer:

• The American Society of Clinical Oncology (ASCO)/Cancer Care Ontario (CCO) made new guidelines about the use of medicine called bone-modifying agents (BMAs) in patients with breast cancer that has spread to their bones (ASCO/CCO [Van Poznak 2017]).
• The guidelines say that patients should start taking a BMA (such as denosumab, pamidronate, or zoledronic acid) when they have metastatic breast cancer to the bone.
• The guidelines do not recommend one BMA over another because there is not enough evidence to support one over the others.
• It is not clear how long patients should keep taking BMAs, but the guidelines suggest they continue indefinitely.
• BMAs can help with pain, but they should not be the only thing used to manage pain.
• Patients should also use other things like supportive care, painkillers, extra treatments, radiation therapy, surgery, and/or systemic anticancer therapy.

Multiple myeloma:

• The American Society of Clinical Oncology (ASCO) has new rules about medicine for bone problems in patients with multiple myeloma (ASCO [Anderson 2018]).
• The rules now say that denosumab can be used instead of zoledronic acid or pamidronate for people with lytic disease.
• Denosumab can also be used for pain control in people who have pain because of osteolytic disease or who are getting other treatments for fractures or almost-fractures.
• People with kidney problems may be better off taking denosumab instead of zoledronic acid.
• The rules say to take the medicine for up to 2 years and then start taking it again if the bone problems come back.
• Denosumab works in a way that can be changed, so don't stop taking it suddenly (see Bone fractures [above] for more information).

Renal impairment:

• Be careful when using this medication in patients with kidney problems or those who need dialysis.
• These patients may be more likely to have low levels of calcium in their blood.
• The dose of the medication does not need to be changed if it is given every 6 months at a dose of 60 mg (Prolia).
• However, giving the medication once a month has not been tested in patients with kidney problems (Xgeva).

Monitoring parameters while using Denosumab:

Recommended monitoring:

• Serum creatinine, serum calcium, phosphorus, and magnesium (especially in the first 14 days of Prolia therapy or during the first weeks of Xgeva therapy)
• Pregnancy test (for females of reproductive potential)
• Signs/symptoms of hypocalcemia, especially for patients predisposed to hypocalcemia
• Signs/symptoms of hypercalcemia, including periodic serum calcium (following discontinuation in patients with giant cell tumor of the bone and patients with growing skeletons)
• Infection or dermatologic reactions
• Routine oral exam (prior to treatment)
• Dental exam if risk factors for ONJ
• Signs/symptoms of hypersensitivity

Recommendations for Osteoporosis

• Recommended monitoring:
  • Bone mineral density (BMD) 1 to 2 years after initiating therapy and every 1 to 2 years (or less frequently if stable) thereafter
  • Annual measurements of height and weight
  • Assessment of chronic back pain
  • Serum calcium and 25(OH)D
  • May consider monitoring biochemical markers of bone turnover

How to administer Denosumab (Prolia, Xgeva):

Administration of Denosumab

• Denosumab should only be given as a subcutaneous injection.
• Do not administer it intravenously, intramuscularly, or intradermally.
• Allow the solution to come to room temperature by leaving it in its original container for about 15 to 30 minutes.
• Do not warm it using any other method.
• Do not use the solution if it appears cloudy, discoloured, or contains excessive particles or foreign matter. A normal solution should be clear and colourless to pale yellow.
• Avoid vigorous shaking of the solution.
• Administer Denosumab via subcutaneous injection in the upper arm, upper thigh, or abdomen.

Administration of Prolia

• If a dose of Prolia is missed, administer it as soon as possible.
• Continue dosing every 6 months from the date of the last injection.

Mechanism of action of Denosumab:

Denosumab is a type of medicine that helps to strengthen bones and prevent bone loss. It works by blocking a protein called RANKL which is responsible for activating cells that break down bones called osteoclasts. When RANKL is blocked by denosumab, osteoclasts are unable to break down bone, which helps to increase bone mass and reduce the risk of fractures.

In these cases, blocking RANKL decreases the activity of osteoclasts, leading to less bone destruction and fewer bone-related events.

By preventing RANKL from activating its receptor on the osteoclast surface, osteoclast precursors, and osteoclast-like giant cells, denosumab can inhibit tumor growth.

Denosumab Brand Names (International):

• Prolia
• Xgeva
• Ranmark

Denosumab Brand Name in Pakistan:

• Prolia
• Xgeva