What is the appropriate workup and treatment for a post-menopausal woman with hypercalcemia?

Laboratory Workup for Elevated Serum Calcium in Post-Menopausal Women

Measure intact parathyroid hormone (iPTH) first—this single test distinguishes between the two causes responsible for 90% of hypercalcemia cases: primary hyperparathyroidism versus malignancy and other PTH-independent causes. 1, 2

Initial Essential Laboratory Panel

• Intact PTH (iPTH): This is the most important initial test and determines the entire diagnostic pathway 2, 3
• Serum albumin: Required to calculate corrected calcium using the formula: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 - Serum albumin (g/dL)] 1
• Ionized calcium: Preferred over corrected calcium to avoid pseudo-hypercalcemia from hemolysis or improper sampling 1
• Serum phosphorus: Helps differentiate causes (low in primary hyperparathyroidism, variable in malignancy) 1
• Serum creatinine and BUN: Essential to assess renal function, as CKD significantly alters calcium metabolism and PTH interpretation 1
• Magnesium: Hypomagnesemia can suppress PTH secretion and must be corrected 1

Algorithmic Approach Based on PTH Level

If PTH is Elevated or Normal (PTH-Dependent Hypercalcemia)

This pattern indicates primary hyperparathyroidism in the vast majority of post-menopausal women 2, 3. With few exceptions, marked increases in PTH confirm this diagnosis 3.

Additional workup for confirmed primary hyperparathyroidism:

• 25-hydroxyvitamin D: Exclude vitamin D deficiency as a secondary cause of elevated PTH 4, 1
• 24-hour urinary calcium: Distinguishes primary hyperparathyroidism from familial hypocalciuric hypercalcemia (FHH), which presents with low urinary calcium excretion 4
• Renal imaging (ultrasound or CT): Assess for nephrolithiasis and nephrocalcinosis 2
• Bone density (DEXA scan): Evaluate for osteoporosis, particularly important in post-menopausal women 2

Pre-operative localization studies (if surgery planned):

• 99mTc-sestamibi parathyroid scan with SPECT/CT: Highly sensitive for localizing parathyroid adenomas 4
• Neck ultrasound: Can be combined with sestamibi for improved sensitivity 4

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

This pattern indicates malignancy or other non-parathyroid causes in over 90% of cases 2, 3.

Mandatory additional workup:

• PTH-related peptide (PTHrP): Elevated in humoral hypercalcemia of malignancy, the most common mechanism in solid tumors 1, 2
• 25-hydroxyvitamin D: Elevated in vitamin D intoxication 1, 2
• 1,25-dihydroxyvitamin D: Elevated in granulomatous diseases (sarcoidosis), some lymphomas, and primary hyperparathyroidism 1, 2
• Serum protein electrophoresis (SPEP) and immunofixation: Screen for multiple myeloma 1
• Complete blood count: Anemia suggests malignancy rather than hyperparathyroidism 5

Important distinction: Measure BOTH 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together for diagnostic accuracy—checking only one can lead to missed diagnoses 1.

Medication and Supplement History

Specifically inquire about:

• Thiazide diuretics: Common cause of mild hypercalcemia 2
• Lithium: Can cause hyperparathyroidism 2
• Calcium supplements >500 mg/day: Excessive intake 1
• Vitamin D supplements >400 IU/day: Risk of toxicity 1
• Vitamin A: High doses cause hypercalcemia 2
• Calcitriol or vitamin D analogs: Cause hypercalcemia in 22.6-43.3% of patients 1

Clinical Context Clues

Features favoring primary hyperparathyroidism:

• Mild hypercalcemia (<12 mg/dL) present for >6 months 5
• History of kidney stones 5
• Hyperchloremic metabolic acidosis 5
• No anemia 5

Features favoring malignancy:

• Rapid onset over days to weeks 2, 5
• Severe hypercalcemia (≥14 mg/dL) 2
• Marked anemia 5
• Constitutional symptoms (weight loss, fatigue) 2
• Never presents with kidney stones or metabolic acidosis 5

Critical Pitfalls to Avoid

• Do not rely on corrected calcium alone: Always measure ionized calcium when possible to avoid misdiagnosis from pseudo-hypercalcemia 1
• Do not check only one vitamin D metabolite: Measure both 25-OH and 1,25-dihydroxy forms together for complete assessment 1
• Do not delay PTH measurement: This is the single most important test and should be obtained immediately with the initial calcium confirmation 2, 3
• Do not assume benign disease in post-menopausal women: While primary hyperparathyroidism is most common, malignancy must be excluded, especially with suppressed PTH 2