What are the management steps for a patient with elevated PTHrP (Parathyroid Hormone-related Protein) levels?

Management of Elevated PTHrP (3.3 pmol/L)

An elevated PTHrP level of 3.3 pmol/L strongly suggests humoral hypercalcemia of malignancy and requires immediate evaluation for underlying malignancy with aggressive treatment of hypercalcemia if present, as PTHrP-mediated hypercalcemia carries a median survival of approximately 1 month after discovery in cancer patients. 1

Immediate Diagnostic Workup

Confirm Hypercalcemia and Assess Severity

• Measure serum calcium (total and ionized if available) and albumin to calculate corrected serum calcium, as concomitant hypoalbuminemia commonly masks the true severity of hypercalcemia 2, 3
• Check serum PTH level, which should be suppressed (<20 pg/mL) in PTHrP-mediated hypercalcemia, distinguishing it from primary hyperparathyroidism 1
• Measure 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D levels, as dual mechanisms (elevated PTHrP plus elevated 1,25-dihydroxyvitamin D) can occur simultaneously in sarcomas and other malignancies 1, 4

Critical caveat: In patients with advanced chronic kidney disease (CKD), specifically request N-terminal PTHrP assays rather than C-terminal assays, as C-terminal PTHrP accumulates with kidney dysfunction and can be falsely elevated in normocalcemic CKD patients without malignancy 5

Malignancy Screening

• Prioritize evaluation for squamous cell carcinomas of lung, head/neck, esophagus, and skin; genitourinary tumors (renal cell carcinoma, ovarian cancer); breast cancer; cholangiocarcinoma; and hematologic malignancies (multiple myeloma, lymphomas), as these have the highest association with PTHrP-mediated hypercalcemia 2, 3, 6
• Obtain CT chest/abdomen/pelvis to evaluate for primary tumor and metastases 1
• Note that skeletal metastases may be absent or minimal in humoral hypercalcemia, as PTHrP circulates systemically rather than acting locally 2, 3

Acute Management of Hypercalcemia

For Moderate to Severe Hypercalcemia (Total Calcium ≥12 mg/dL)

• Initiate aggressive IV crystalloid hydration with normal saline (200-300 mL/hour) to restore intravascular volume and promote calciuresis 1
• Administer loop diuretics (furosemide 20-40 mg IV) only after adequate volume repletion to enhance calcium excretion 1
• Give IV bisphosphonates as primary therapy: zoledronic acid 4 mg IV over 15 minutes OR pamidronate 60-90 mg IV over 2-4 hours 1, 2, 3
• Consider calcitonin (4-8 IU/kg subcutaneously every 6-12 hours) as a temporizing measure for rapid calcium reduction while awaiting bisphosphonate effect (onset 24-48 hours) 1

For Acute Symptomatic Severe Hypercalcemia (Total Calcium ≥14 mg/dL or Ionized Calcium ≥10 mg/dL)

• Initiate hypertonic 3% saline IV in addition to aggressive hydration 1

Monitoring During Acute Treatment

• Check serum calcium and ionized calcium every 1-2 weeks until stable 1
• Monitor serum phosphate, as levels typically decrease after bisphosphonate administration due to decreased phosphate release from bone; phosphate supplementation may be needed 3

Definitive Cancer-Directed Therapy

The most effective long-term management is treatment of the underlying malignancy, as chemotherapy can reduce tumor burden, decrease PTHrP secretion, and normalize calcium levels. 7

• For PTHrP-secreting cholangiocarcinoma: cisplatin plus gemcitabine has demonstrated efficacy in reducing tumor size and PTHrP levels 7
• Immunohistochemical staining for PTHrP on tumor tissue can confirm the source when multiple malignancies coexist 7, 6
• The correlation between corrected serum calcium and PTHrP levels (r=0.476, p<0.001) suggests that serial PTHrP measurements may help monitor treatment response 6

Special Considerations and Pitfalls

When PTHrP is Elevated but PTH is Not Suppressed

• If PTH is >26 ng/L, PTHrP testing is usually uninformative and the elevated PTHrP may be a false positive or incidental finding 8
• Consider alternative diagnoses including primary hyperparathyroidism coexisting with malignancy (occurs in 3.9% of hypercalcemic patients) 6

Avoid Common Errors

• Do not delay malignancy workup based on absence of bone metastases, as 55.9% of PTHrP-mediated hypercalcemia cases lack bony involvement 6
• Do not use C-terminal PTHrP assays in patients with eGFR <60 mL/min/1.73m², as these accumulate with renal dysfunction 5
• Avoid calcium-based phosphate binders if the patient has CKD, as these worsen hypercalcemia 1

Prognosis

• PTHrP-mediated hypercalcemia indicates advanced malignancy with poor prognosis (median survival approximately 1 month in lung cancer) 1
• However, survival time does not correlate with serum calcium or PTHrP levels, and aggressive symptom management remains warranted regardless of prognosis 6