Hypercalcemia of Malignancy: PTH and PTHrP Testing
Yes, PTH is expected to be suppressed (low or undetectable) in hypercalcemia of malignancy, and measuring PTHrP is the appropriate next diagnostic step to confirm the most common mechanism of malignancy-associated hypercalcemia. 1
Diagnostic Algorithm for Hypercalcemia of Malignancy
Initial Laboratory Evaluation
When hypercalcemia is identified, the first critical step is measuring intact PTH (iPTH) to distinguish PTH-dependent from PTH-independent causes. 1, 2, 3
In hypercalcemia of malignancy, PTH is characteristically suppressed because the elevated calcium appropriately inhibits parathyroid gland secretion. 1 This contrasts sharply with primary hyperparathyroidism, where PTH is elevated or inappropriately normal despite hypercalcemia. 2
Complete Diagnostic Panel
Once suppressed PTH confirms PTH-independent hypercalcemia, obtain the following measurements simultaneously: 1, 2
- PTHrP (parathyroid hormone-related protein)
- 1,25-dihydroxyvitamin D (calcitriol)
- 25-hydroxyvitamin D
- Serum calcium (corrected for albumin or ionized calcium)
- Albumin
- Phosphorus
- Magnesium
- Creatinine and BUN
PTHrP as the Next Step
Measuring PTHrP after finding suppressed PTH is the logical next step because PTHrP-mediated hypercalcemia is the most common mechanism of malignancy-associated hypercalcemia, accounting for the majority of cases. 1, 4 PTHrP is elevated in plasma or urine in most hypercalcemic cancer patients when measured with appropriate assays. 4
Mechanism-Specific Laboratory Patterns
PTHrP-Mediated Hypercalcemia (Most Common)
- Suppressed iPTH (low or undetectable)
- Elevated PTHrP
- Low or normal 1,25-dihydroxyvitamin D (calcitriol)
- Normal or low 25-hydroxyvitamin D 1
This pattern is most commonly seen in squamous cell carcinomas (particularly lung), neuroendocrine tumors, and various other solid malignancies. 1, 5
Calcitriol-Mediated Hypercalcemia (Less Common)
This mechanism occurs in lymphomas and granulomatous diseases due to unregulated 1-alpha-hydroxylase activity in activated macrophages or tumor cells. 6, 2
Local Osteolytic Hypercalcemia
- Suppressed iPTH
- Normal PTHrP
- Normal vitamin D metabolites 1
This occurs with extensive bone metastases, particularly in breast cancer and multiple myeloma. 4
Critical Clinical Considerations
Prognostic Implications
The median survival after discovery of hypercalcemia of malignancy in lung cancer patients is approximately 1 month, making this a medical emergency requiring prompt diagnosis and treatment. 1 The severity and rapidity of onset should guide urgency of workup and treatment.
Rare Dual Mechanism Cases
Be aware that simultaneous PTHrP and calcitriol overproduction can occur, though this is uncommon. 7 If initial treatment targeting one mechanism fails, consider measuring both PTHrP and 1,25-dihydroxyvitamin D even if one was initially normal, as dual mechanisms have diagnostic and therapeutic consequences. 7
PTHrP Levels During Treatment
PTHrP levels do not consistently decrease with successful calcium-lowering treatment using bisphosphonates or other therapies. 8, 9 Therefore, PTHrP should be used for initial diagnosis, not for monitoring treatment response. Monitor serum calcium, renal function, and electrolytes instead to assess treatment effectiveness. 6
Interestingly, elevated PTHrP levels predict less effective calcium lowering with bisphosphonates, so patients with high PTHrP may require more aggressive or combination therapy. 9
Common Pitfalls to Avoid
Do not assume normal PTHrP excludes malignancy-associated hypercalcemia—other mechanisms (calcitriol production, local osteolysis) can cause hypercalcemia with suppressed PTH and normal PTHrP. 1, 7
Do not delay treatment while awaiting PTHrP results if the patient has severe hypercalcemia (>14 mg/dL) or symptomatic hypercalcemia—initiate IV hydration and bisphosphonates immediately. 1, 6
Do not use PTHrP levels to monitor treatment response—the levels remain elevated despite successful calcium lowering and do not correlate with treatment efficacy. 8, 9
Do not forget to measure both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D—the relationship between these two provides critical diagnostic information, particularly for distinguishing PTHrP-mediated from calcitriol-mediated hypercalcemia. 2