What are the causes of hypercalcemia, especially in older adults or individuals with a history of malignancy?

Causes of Hypercalcemia

Primary Causes

Primary hyperparathyroidism and malignancy account for approximately 90% of all hypercalcemia cases. 1, 2

PTH-Dependent Hypercalcemia (Elevated or Normal PTH)

• Primary hyperparathyroidism is characterized by elevated or inappropriately normal PTH levels with hypercalcemia, representing the most common cause in ambulatory patients 1
• Tertiary hyperparathyroidism occurs in chronic kidney disease patients with persistent hypercalcemic hyperparathyroidism despite optimized medical therapy 3
• Familial hypocalciuric hypercalcemia should be considered in patients with mild hypercalcemia and inappropriately normal PTH 4
• Lithium therapy can cause PTH-dependent hypercalcemia 2, 4

PTH-Independent Hypercalcemia (Suppressed PTH <20 pg/mL)

Malignancy-Related (Most Common in Hospitalized Patients)

• Humoral hypercalcemia of malignancy is mediated by parathyroid hormone-related protein (PTHrP), accounting for 80% of malignancy-associated hypercalcemia, most commonly in squamous cell carcinomas and renal cell carcinoma 1, 5, 6
• Osteolytic bone metastases cause local bone destruction with calcium release, accounting for 20% of malignancy-associated cases, particularly in breast cancer, lung cancer, and multiple myeloma 1, 5, 6
• 1,25-dihydroxyvitamin D-producing lymphomas cause hypercalcemia through increased intestinal calcium absorption 1, 5

Vitamin D-Related Disorders

• Vitamin D intoxication from excessive supplementation (>400 IU/day) leads to increased intestinal calcium absorption 1, 2
• Granulomatous diseases, particularly sarcoidosis, cause hypercalcemia due to increased 1,25-dihydroxyvitamin D production by activated macrophages 1, 2, 4

Endocrine Disorders

• Thyrotoxicosis increases bone turnover and calcium release 2, 4
• Hypocalcemia in 22q11.2 deletion syndrome can paradoxically lead to iatrogenic hypercalcemia from overcorrection with calcitriol, especially with dehydration or treatment compliance changes 7

Medication-Induced

• Thiazide diuretics reduce urinary calcium excretion 2, 4
• Calcium-based phosphate binders in chronic kidney disease patients, particularly those with low-turnover bone disease, frequently cause hypercalcemia 1
• Calcitriol and vitamin D analogues (paricalcitol) cause hypercalcemia in 22.6-43.3% of CKD patients in clinical trials 3
• Denosumab discontinuation can cause rebound hypercalcemia 2
• Immune checkpoint inhibitors are emerging causes, though accounting for <1% of cases 2
• Patiromer (potassium binder) causes hypercalcemia due to its calcium-sorbitol counterion 3

Other Causes

• Immobilization increases bone resorption, particularly in patients with high bone turnover 2, 4
• Milk-alkali syndrome from excessive calcium and alkali ingestion 4
• Williams syndrome is associated with idiopathic infantile hypercalcemia 1

Special Considerations in Older Adults and Malignancy Patients

In older adults with a history of malignancy presenting with hypercalcemia, malignancy-associated hypercalcemia should be the primary consideration, as it typically presents with markedly elevated calcium levels (often >14 mg/dL) and severe symptoms. 2, 5

• Hypercalcemia of malignancy carries a poor prognosis with median survival of approximately 1 month, making prompt diagnosis critical 3, 2
• These patients usually present with rapid onset over days to weeks, causing nausea, vomiting, dehydration, confusion, somnolence, and potentially coma 2, 5
• PTHrP should be measured when PTH is suppressed in cancer patients, as it is elevated in the majority of malignancy-associated cases 1, 5

Critical Diagnostic Pitfall

• Always measure intact PTH as the most important initial test to distinguish PTH-dependent from PTH-independent causes—this single test narrows the differential diagnosis dramatically 1, 2, 4
• In older adults, do not assume all hypercalcemia is malignancy-related; approximately 10% may have undiagnosed primary hyperparathyroidism requiring different management 6
• Measure ionized calcium when possible, as total and corrected calcium are often inaccurate, particularly in patients with abnormal albumin levels 3, 4