What Causes Hypercalcemia
The two most common causes of hypercalcemia are primary hyperparathyroidism (accounting for approximately 90% of outpatient cases) and malignancy (responsible for most inpatient cases and 10-25% of patients with cancer). 1, 2, 3
Primary Causes by Clinical Setting
Outpatient Hypercalcemia
- Primary hyperparathyroidism is the leading cause in ambulatory patients, characterized by elevated or inappropriately normal PTH levels despite hypercalcemia 1, 2
- This condition results from autonomous parathyroid hormone secretion, leading to increased bone resorption and calcium absorption 3
Inpatient Hypercalcemia
- Malignancy-associated hypercalcemia dominates in hospitalized patients, with particularly poor prognosis (median survival approximately 1 month) 1
- Two distinct mechanisms occur in malignancy:
- Humoral hypercalcemia: PTH-related protein (PTHrP) secretion by tumors (squamous cell lung cancer, head/neck cancers, renal cell carcinoma, ovarian cancer) stimulates systemic bone resorption even without skeletal metastases 2, 4
- Local osteolytic hypercalcemia: Direct tumor invasion of bone (breast cancer, multiple myeloma) releases local factors that activate osteoclasts 2, 4
Additional Important Causes
Vitamin D-Related Disorders
- Granulomatous diseases (particularly sarcoidosis) cause hypercalcemia through increased production of 1,25-dihydroxyvitamin D by activated macrophages 2, 3
- Vitamin D intoxication from excessive supplementation leads to increased intestinal calcium absorption 5, 2
- Lymphomas can produce vitamin D metabolites, causing hypercalcemia 3, 6
Medication-Induced Hypercalcemia
- Thiazide diuretics reduce renal calcium excretion 3, 7
- Lithium alters parathyroid gland calcium sensing 7
- Calcium and vitamin D supplements, particularly in patients with chronic kidney disease and low-turnover bone disease, frequently cause hypercalcemia 5
- Vitamin D toxicity typically occurs at 25(OH)D levels >150 ng/mL (>375 nmol/L) 5
Chronic Kidney Disease
- Patients with CKD receiving calcium-based phosphate binders and/or active vitamin D sterols frequently develop hypercalcemia 5
- Spontaneous hypercalcemia also occurs in CKD patients, particularly those with low-turnover bone disease 5
- Tertiary hyperparathyroidism in advanced CKD can cause hypercalcemia 7
Endocrine Disorders
- Thyrotoxicosis increases bone turnover and calcium release 7
- Williams syndrome causes idiopathic infantile hypercalcemia 2
Other Causes
- Familial hypocalciuric hypercalcemia (FHH) is a benign genetic condition that must be distinguished from primary hyperparathyroidism before considering surgery 7, 8
- Immobilization reduces mechanical stress on bone, increasing resorption 3, 7
- Milk-alkali syndrome from excessive calcium and alkali intake 7
Pathophysiologic Mechanism
The final common pathway involves excessive bone resorption by osteoclasts, releasing calcium into the bloodstream 9, 4. This triggers:
- Polyuria and gastrointestinal disturbances leading to progressive dehydration 9, 4
- Decreased glomerular filtration rate 9, 4
- Increased renal calcium reabsorption, creating a vicious cycle of worsening hypercalcemia 9, 4