Can denosumab (Prolia) cause hypercalcemia?

Denosumab and Hypercalcemia

Denosumab itself does not cause hypercalcemia during active treatment; however, severe rebound hypercalcemia is a well-documented and potentially life-threatening complication that occurs after denosumab discontinuation, particularly in pediatric patients and those with underlying conditions predisposing to hypercalcemia.

Hypercalcemia Risk Profile

During Active Treatment

• Denosumab is an antiresorptive agent that inhibits bone resorption and typically causes hypocalcemia, not hypercalcemia 1
• The FDA label specifically warns about severe symptomatic hypocalcemia as a primary concern during treatment, with fatal cases reported 1
• In patients with hypercalcemia of malignancy, denosumab effectively decreases calcium levels and is used therapeutically for this indication 2, 3, 4

After Treatment Discontinuation

The critical risk period is post-discontinuation, when rebound hypercalcemia can occur:

• Rebound increased bone turnover has led to severe hypercalcemia in several pediatric patients after denosumab cessation 2
• The FDA label explicitly warns about hypercalcemia following treatment discontinuation in patients with giant cell tumor of bone and in patients with growing skeletons 1
• This rebound effect typically occurs 3-9 months after the last denosumab dose 5, 6, 7, 8

Mechanism of Rebound Hypercalcemia

• Denosumab's effect on bone turnover is rapidly reversible after cessation, unlike bisphosphonates which incorporate into bone matrix 2
• Upon discontinuation, there is a marked rebound increase in bone resorption with dramatically elevated bone turnover markers 5, 8
• This massive bone resorption releases calcium into the circulation, causing hypercalcemia 5, 8

High-Risk Populations

Pediatric patients with growing skeletons are at highest risk:

• Multiple case reports document severe hypercalcemia in children after denosumab cessation 2, 7
• The FDA specifically warns about this complication in skeletally immature patients 1

Adults with underlying hypercalcemic conditions:

• Patients with primary hyperparathyroidism can develop severe hypercalcemia when the rebound effect compounds their baseline condition 5
• Patients with metastatic bone disease are at risk for rebound hypercalcemia after long-term denosumab use 6, 8

Clinical Presentation

Symptoms of rebound hypercalcemia include:

• Thirst, appetite loss, worsening overall health 8
• Bone pain (particularly vertebral) 5, 8
• Symptomatic hypercalcemia requiring hospitalization 5, 6, 7

Laboratory findings:

• Elevated serum calcium (can reach 3.35 mmol/L or higher) 5
• Suppressed PTH levels 6
• Markedly elevated bone turnover markers 5, 8
• Elevated fibroblast growth factor 23 (FGF-23) may serve as a surrogate marker 8

Management of Rebound Hypercalcemia

When rebound hypercalcemia occurs after denosumab discontinuation:

1. Acute treatment with intravenous bisphosphonates (zoledronic acid) is the most effective approach 5, 6, 7

   • May require multiple doses to achieve sustained normocalcemia 6
   • Single dose of zoledronic acid can rapidly normalize calcium and suppress bone turnover markers 5, 7

2. Supportive measures:

   • Intravenous hydration with normal saline 7, 4
   • Loop diuretics (after volume repletion) 7
   • Calcitonin for acute management 7, 8

3. Re-administration of denosumab can rapidly decrease serum calcium in some cases 5

Prevention Strategies

To prevent rebound hypercalcemia when discontinuing denosumab:

• Transition to bisphosphonate therapy after 5 years of denosumab treatment in adults to reduce or prevent rebound bone turnover 2
• Monitor calcium levels for at least 9 months after the last denosumab dose, particularly in high-risk patients 1, 5, 6
• Consider continuation of denosumab rather than discontinuation in patients at high risk 2
• In patients with primary hyperparathyroidism, definitive surgical treatment (parathyroidectomy) should be considered before or shortly after denosumab discontinuation 5

Critical Caveats

• The rebound effect is associated with a marked increase in vertebral fracture risk in addition to hypercalcemia 2
• There is no established optimal bisphosphonate regimen post-denosumab, though zoledronic acid appears most effective based on case reports 2, 5, 6, 7
• Avoid denosumab discontinuation in pediatric patients whenever possible due to severe rebound risk 2, 1
• Patients with renal impairment require careful calcium monitoring as they have greater risk of both hypocalcemia during treatment and potentially more severe rebound effects 1