What are the recommended denosumab (Xgeva) dosing regimens for osteoporosis, bone metastases from solid tumours, and unresectable giant‑cell tumour of bone, and what calcium/vitamin D supplementation and monitoring are required?

Denosumab Dosing Regimens

Osteoporosis (Prolia)

For osteoporosis prevention and treatment, denosumab is administered as 60 mg subcutaneously every 6 months, with mandatory daily calcium (1,000-1,200 mg) and vitamin D (400-800 IU) supplementation throughout treatment. 1, 2

Pre-Treatment Requirements

• Measure serum 25-hydroxyvitamin D and correct to at least 20 ng/mL before initiating therapy to reduce hypocalcemia risk 2
• Baseline bone mineral density assessment with vertebral fracture analysis 2
• Mandatory baseline dental examination to reduce osteonecrosis of the jaw (ONJ) risk 1, 2
• Measure serum calcium before starting treatment 2

Ongoing Monitoring

• Check serum calcium before each 6-month injection 2
• Monitor vitamin D status intermittently during treatment 2, 3
• Continue calcium (1,000-1,200 mg daily) and vitamin D (600-800 IU daily, minimum 400 IU) supplementation throughout therapy 2
• Regular dental care and oral health monitoring 1

Critical Safety Warning

Never discontinue denosumab abruptly—this causes rebound bone loss and increased fracture risk. If stopping denosumab after more than 6 months, transition to bisphosphonate therapy to suppress rebound osteolysis. 3

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Bone Metastases from Solid Tumors (Xgeva)

For prevention of skeletal-related events in bone metastases, denosumab is dosed at 120 mg subcutaneously every 4 weeks, with mandatory calcium (500-1,000 mg daily) and vitamin D (400-800 IU daily) supplementation. 1, 2

Pre-Treatment Requirements

• Correct any pre-existing hypocalcemia before initiating therapy 1, 4
• Measure serum calcium—hypocalcemia occurs in 13% with denosumab versus 6% with zoledronic acid 2, 3
• Evaluate serum vitamin D levels and correct deficiency 2, 3
• Mandatory baseline dental examination to reduce ONJ risk 1, 2, 4
• Assess renal function (creatinine, estimated creatinine clearance), though denosumab requires no dose adjustment for renal impairment 2, 3

Ongoing Monitoring

• Monitor serum calcium before each injection, with increased frequency after the first 2-3 doses 2, 4
• Unlike bisphosphonates, denosumab does not require renal function monitoring before each dose 3
• Continue mandatory calcium (500-1,000 mg daily) and vitamin D (400-800 IU daily) supplementation 1, 2
• Close oral health monitoring throughout treatment 2, 3

Treatment Duration

• Continue treatment until evidence of substantial decline in general performance status 2
• For patients with stable disease at 2 years, some retrospective studies support extending intervals from 4-weekly to 8-weekly dosing 1

Key Advantage Over Bisphosphonates

Denosumab is the agent of choice in patients with renal impairment (creatinine clearance <60 mL/min) because it requires no dose adjustment and has lower renal toxicity compared to zoledronic acid. 4, 3

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Unresectable Giant Cell Tumor of Bone (Xgeva)

For unresectable or surgically morbid giant cell tumor of bone, denosumab is dosed at 120 mg subcutaneously with loading doses on Days 1,8, and 15, then every 4 weeks thereafter. 1

Indications for Use

• Surgery is not possible or would be unacceptably morbid 1
• Patients with metastases 1
• Selected cases before surgery to solidify soft tissue component, facilitating resection and reducing recurrence risk 1

Pre-Treatment Requirements

• All patients require daily calcium and vitamin D supplements 1
• Mandatory contraception—patients must avoid pregnancy using adequate contraception 1
• Baseline dental examination 1

Ongoing Monitoring

• Regular monitoring for significant side effects including ONJ 1
• Calcium and vitamin D supplementation throughout treatment 1

Surgical Considerations After Denosumab

If surgery is planned after denosumab treatment, complete resection is usually preferred over curettage. Curettage after denosumab is difficult and associated with higher local recurrence risk, particularly in sacral tumors. 1, 5

Long-Term Treatment

• Patients with metastatic disease may require life-long treatment 1
• Retrospective studies support extending intervals from 4-weekly to 8-weekly in patients with stable disease at 2 years 1

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Special Clinical Scenarios

Bisphosphonate-Refractory Hypercalcemia of Malignancy

For hypercalcemia refractory to bisphosphonates, denosumab is dosed at 120 mg subcutaneously on Days 1,8,15, and 29, then every 4 weeks thereafter. This intensive loading schedule differs from standard bone metastases dosing. 4

• Denosumab has FDA approval specifically for this indication with 64% response rate 4
• Intensive calcium monitoring is critical given 13% hypocalcemia risk, especially after first 2-3 doses 4
• Mandatory calcium (1,000-1,500 mg daily) and vitamin D (400-800 IU daily) supplementation 4

Patients with Advanced Chronic Kidney Disease

Patients with creatinine clearance <30 mL/min face higher hypocalcemia risk and require management by providers experienced in CKD-mineral bone disorder. 2, 4

• These patients may require activated vitamin D (calcitriol) supplementation in addition to standard calcium and vitamin D 2
• Severe hypocalcemia (<1.8 mmol/L or <7.2 mg/dL) requires hospitalization with IV calcium gluconate infusion at 1-2 mg elemental calcium/kg/hour with cardiac monitoring 2

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Common Pitfalls to Avoid

Hypocalcemia Management

Failure to correct hypocalcemia before starting denosumab can lead to severe symptomatic hypocalcemia. 2, 4 Severe hypocalcemia typically presents 4-35 days after initial or second denosumab treatment and may require hospitalization with prolonged IV calcium treatment. 2

Dental Complications

Neglecting dental evaluation before initiation increases ONJ risk. 2, 4 Complete any planned invasive dental procedures before starting denosumab, and suspend denosumab if urgent dental surgery is required during treatment. 4

Discontinuation Risk

Abrupt discontinuation without follow-up therapy causes rebound bone loss, increased fracture risk, and potentially worsening hypercalcemia. 4, 3 If discontinuing denosumab for more than 6 months, transition to bisphosphonate therapy. 3

Vitamin D Deficiency

A case report documented severe hypocalcemia requiring repeated IV calcium doses in a patient with metastatic prostate cancer who received denosumab with unrecognized vitamin D deficiency. 6 Always measure and correct vitamin D levels before initiating therapy.