Why does metastatic cancer cause hypercalcemia?

Why Calcium Levels Are Elevated in Metastatic Cancer

Metastatic cancer causes hypercalcemia primarily through tumor secretion of parathyroid hormone-related protein (PTHrP), which mimics normal parathyroid hormone and drives excessive bone resorption by osteoclasts, releasing calcium into the bloodstream. 1

Primary Mechanisms of Malignancy-Associated Hypercalcemia

1. Humoral Hypercalcemia (80% of cases)

PTHrP-mediated hypercalcemia is the dominant mechanism, accounting for the vast majority of cases. 2

• Tumor cells produce PTHrP, which binds to the same receptors as parathyroid hormone, stimulating osteoclast activity and increasing bone resorption. 1
• This mechanism is characterized by suppressed intact PTH levels (<20 pg/mL) with elevated PTHrP, distinguishing it from primary hyperparathyroidism. 3, 4
• The biochemical pattern shows low or normal 1,25-dihydroxyvitamin D (calcitriol) levels alongside the suppressed PTH. 3

Calcitriol-mediated hypercalcemia occurs less frequently, particularly in lymphomas and some solid tumors. 4

• Certain malignancies (especially non-Hodgkin's lymphoma) produce excess 1,25-dihydroxyvitamin D, increasing intestinal calcium absorption. 4
• The laboratory profile shows suppressed PTH, low/normal 25-hydroxyvitamin D, and elevated 1,25-dihydroxyvitamin D. 4
• This mechanism responds specifically to corticosteroid therapy. 3

2. Local Osteolytic Hypercalcemia (20% of cases)

Direct bone destruction by metastatic tumor cells releases calcium from the skeletal matrix. 2

• Tumor cells within bone produce cytokines (including interleukins and prostaglandins) that increase RANKL production by osteoblastic cells, activating osteoclasts. 1
• As bone matrix breaks down, bone-derived growth factors are released, creating a "vicious cycle" that promotes further tumor growth and bone destruction. 1
• Multiple myeloma exemplifies this mechanism, with direct bone invasion and secretion of osteoclast-activating factors causing extensive lytic lesions. 4

The Vicious Cycle of Bone Metastasis

Metastatic tumor cells and the bone microenvironment engage in multidirectional interactions that perpetuate both tumor growth and calcium release. 1

• Disseminated tumor cells colonize the bone marrow, particularly the hematopoietic stem cell niche, where they may remain dormant for years. 1
• Once activated, tumor cells secrete parathyroid hormone-related peptide, prostaglandins, and interleukins that stimulate RANKL production. 1
• RANKL activates osteoclasts, leading to bone resorption and release of bone-derived factors (including calcium and growth factors). 1
• These released factors fuel tumor cell proliferation, completing the self-sustaining cycle. 1

Cancer Types Most Commonly Associated with Hypercalcemia

Hypercalcemia occurs in 10-25% of cancer patients, with marked variation by tumor type. 3, 4

• Squamous cell lung cancer has the highest frequency of hypercalcemia among solid tumors. 3
• Breast cancer (70% develop bone metastases) commonly presents with hypercalcemia, usually related to widespread osteolytic lesions. 1, 5
• Multiple myeloma (95% have bone involvement) frequently causes hypercalcemia through extensive osteolytic destruction. 1
• Renal cell carcinoma (40% develop bone metastases) often produces PTHrP, causing humoral hypercalcemia. 1
• Prostate cancer (85% develop bone metastases) causes hypercalcemia despite predominantly osteoblastic-appearing lesions, because underlying osteoclastic activity remains high. 1

Clinical Significance and Prognosis

Hypercalcemia of malignancy indicates advanced disease and carries a poor prognosis. 4

• In lung cancer patients, median survival after hypercalcemia diagnosis is approximately one month. 3, 4
• Breast cancer patients with bone metastases who develop skeletal-related events (including hypercalcemia) have median survival of only 7 months, compared to 16 months for those with bone metastases alone. 1
• Hypercalcemia is often a paraneoplastic phenomenon that can occur even without radiographically evident bone metastases, particularly in PTHrP-mediated cases. 1

Why Hypercalcemia Develops Despite Normal Homeostatic Mechanisms

The calcium-sensing receptor on parathyroid cells appropriately suppresses PTH secretion in response to elevated serum calcium, but this normal feedback cannot overcome the tumor-driven mechanisms. 6

• Tumor-produced PTHrP bypasses normal parathyroid regulation, continuously stimulating bone resorption regardless of serum calcium levels. 2
• The kidneys' capacity for calcium excretion becomes overwhelmed, particularly when tumor-induced hypercalcemia causes polyuria and dehydration, creating a self-perpetuating cycle. 3
• Volume depletion reduces glomerular filtration rate, further impairing calcium excretion and worsening hypercalcemia. 3

Common Pitfalls in Understanding Malignancy-Associated Hypercalcemia

Bone metastases visible on imaging are rarely the sole cause of hypercalcemia—humoral factors predominate even when skeletal lesions are present. 7

• Clinicians often assume that extensive bone metastases directly cause hypercalcemia, but PTHrP-mediated mechanisms are responsible in most cases. 2
• Even "osteoblastic" metastases (such as prostate cancer) involve significant osteoclastic activity, as demonstrated by elevated bone resorption markers. 1
• Hypercalcemia can occur without any radiographic bone metastases, particularly in squamous cell carcinomas producing PTHrP. 1

Combined mechanisms may coexist in the same patient, particularly in cases of treatment-resistant hypercalcemia. 8

• Simultaneous PTHrP and calcitriol overproduction has been documented, requiring measurement of both mediators for complete diagnosis. 9
• Standard testing algorithms that measure only PTH and PTHrP may miss calcitriol-mediated components. 9