What is the cause of hypercalcemia with decreased Parathyroid Hormone (PTH) and elevated Parathyroid Hormone-related Protein (PTHrP)?

Hypercalcemia with Decreased PTH and Elevated PTHrP: Malignancy-Associated Hypercalcemia

The combination of decreased PTH, elevated PTHrP, and decreased vitamin D 25-OH indicates malignancy-associated hypercalcemia, specifically humoral hypercalcemia of malignancy (HHM). This is the most common cause of hypercalcemia in hospitalized patients after primary hyperparathyroidism and carries a poor prognosis with median survival of approximately 1 month 1.

Diagnostic Interpretation

The laboratory pattern you describe is pathognomonic for malignancy:

• Suppressed PTH excludes primary hyperparathyroidism and confirms PTH-independent hypercalcemia 1
• Elevated PTHrP is the hallmark of humoral hypercalcemia of malignancy, found in 76.3% of patients with malignancy-associated hypercalcemia 2
• Decreased 25-hydroxyvitamin D is expected as the hypercalcemia suppresses PTH, which normally stimulates 1,25-dihydroxyvitamin D production 3

Pathophysiology

In humoral hypercalcemia, tumor cells secrete PTHrP systemically, which activates osteoclasts and stimulates bone resorption without requiring skeletal metastases 4. PTHrP binds to the same PTH receptor, mimicking PTH's effects on bone and kidney, causing:

• Increased osteoclastic bone resorption and calcium release 4
• Enhanced renal calcium reabsorption 4
• Suppression of endogenous PTH due to negative feedback from hypercalcemia 5

The decreased vitamin D 25-OH reflects the suppressed PTH, which normally drives conversion to the active 1,25-dihydroxyvitamin D form 3.

Associated Malignancies

PTHrP-mediated hypercalcemia occurs most commonly with:

• Squamous cell carcinomas of lung, head and neck, or esophagus (100% PTHrP elevation rate) 2
• Genitourinary tumors including renal cell carcinoma and ovarian cancer 4
• Breast carcinoma 2
• Cholangiocarcinoma 2

Importantly, skeletal metastases may be absent or minimal in these patients, as PTHrP acts systemically rather than locally 4. In one series, only 44.1% of patients with elevated PTHrP had bony metastases, and there was no correlation between high PTHrP and presence of bone metastases 2.

Clinical Implications

This diagnosis indicates:

• Active malignancy requiring urgent oncologic evaluation if not already diagnosed 1
• Poor prognosis with median survival approximately 1 month from hypercalcemia onset 1
• Need for aggressive calcium-lowering therapy as PTHrP levels remain elevated despite bisphosphonate treatment 6

The severity of hypercalcemia correlates with PTHrP levels (r = 0.476, p < 0.001), though survival time does not differ significantly between high and normal PTHrP groups once hypercalcemia develops 2.

Management Approach

Initial treatment priorities:

1. Aggressive IV hydration with crystalloid fluids (not containing calcium) to restore intravascular volume 1
2. Bisphosphonates (zoledronic acid or pamidronate) as first-line pharmacologic therapy to inhibit osteoclastic bone resorption 1, 4
3. Loop diuretics only after volume restoration 1

Critical caveat: Patients with elevated PTHrP respond less effectively to bisphosphonates than those with normal PTHrP (mean calcium 2.89 vs 2.51 mmol/L at day 6), and PTHrP levels remain unchanged despite calcium-lowering therapy 6. This necessitates definitive treatment of the underlying malignancy for sustained calcium control 7.

Differential Consideration

Rare variant: In exceptional cases, non-Hodgkin's lymphoma can cause co-secretion of both PTHrP and 1,25-dihydroxyvitamin D, which would present with elevated (not decreased) 1,25-dihydroxyvitamin D despite suppressed PTH 7. However, your patient's decreased vitamin D 25-OH makes this unlikely and points to the classic humoral hypercalcemia syndrome.