What causes hypercalcemia in malignancy (cancer)?

From the Guidelines

Hypercalcemia in cancer is primarily caused by tumor-related factors that disrupt normal calcium regulation, with the most common mechanism being the production of parathyroid hormone-related protein (PTHrP) by tumor cells, as seen in squamous cell carcinomas, breast cancer, and renal cell carcinoma 1.

Causes of Hypercalcemia in Malignancy

The causes of hypercalcemia in malignancy can be multifactorial, including:

• Production of parathyroid hormone-related protein (PTHrP) by tumor cells, which mimics the action of parathyroid hormone and increases bone resorption, releasing calcium into the bloodstream
• Direct bone invasion by cancer cells, which activates osteoclasts to break down bone tissue, commonly seen in multiple myeloma and breast cancer metastases
• Production of substances like vitamin D (1,25-dihydroxyvitamin D) that increase intestinal calcium absorption, particularly in lymphomas
• Secretion of cytokines and growth factors such as interleukin-1, interleukin-6, and tumor necrosis factor that stimulate osteoclast activity
• Immobility in advanced cancer patients, which can worsen hypercalcemia by promoting bone resorption

Treatment of Hypercalcemia

Treatment of hypercalcemia typically involves hydration with intravenous fluids, bisphosphonates like zoledronic acid (4mg IV) or pamidronate (60-90mg IV), calcitonin for rapid but short-term effect, and addressing the underlying malignancy through appropriate cancer therapy 1. Some key points to consider in the treatment of hypercalcemia include:

• The use of bisphosphonates, such as zoledronic acid, which has been shown to reduce skeletal-related events and improve quality of life in patients with multiple myeloma 1
• The importance of monitoring renal function and performing a dental examination before starting bisphosphonate therapy to minimize the risk of osteonecrosis of the jaw (ONJ) 1
• The consideration of denosumab as an alternative to bisphosphonates, particularly in patients with renal disease 1

From the FDA Drug Label

Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysiologic derangement in hypercalcemia of malignancy (HCM, tumor-induced hypercalcemia) and metastatic bone disease. Patients who have hypercalcemia of malignancy can generally be divided into two groups according to the pathophysiologic mechanism involved: humoral hypercalcemia and hypercalcemia due to tumor invasion of bone In humoral hypercalcemia, osteoclasts are activated and bone resorption is stimulated by factors such as parathyroid hormone-related protein, which are elaborated by the tumor and circulate systemically. Extensive invasion of bone by tumor cells can also result in hypercalcemia due to local tumor products that stimulate bone resorption by osteoclasts.

The causes of hypercalcemia in malignancy are:

• Osteoclastic hyperactivity resulting in excessive bone resorption
• Humoral hypercalcemia: osteoclasts are activated and bone resorption is stimulated by factors such as parathyroid hormone-related protein
• Hypercalcemia due to tumor invasion of bone: extensive invasion of bone by tumor cells resulting in hypercalcemia due to local tumor products that stimulate bone resorption by osteoclasts 2

From the Research

Causes of Hypercalcemia in Malignancy

• Hypercalcemia of malignancy is usually caused by abnormal calcium use resulting from bone resorption, intestinal absorption, or renal excretion 3
• Several major mechanisms are responsible for the development of hypercalcemia of malignancy, including:
  • Parathyroid hormone-related peptide-mediated humoral hypercalcemia 4, 5
  • Osteolytic metastases-related hypercalcemia 4, 5
  • 1,25 Vitamin D-mediated hypercalcemia 4, 5
  • Parathyroid hormone-mediated hypercalcemia in patients with parathyroid carcinoma and extra parathyroid cancers 4
• The majority of cases are humoral in etiology and related to parathyroid hormone-related protein (PTHrP) 5
• Approximately 20% of cases are the result of direct bone metastasis with extra-renal 1,25-dihydroxyvitamin D (calcitriol) and ectopic parathyroid hormone production likely accounting for less than 1% of cases 5

Clinical Manifestations and Diagnosis

• Hypercalcemia of malignancy usually presents with markedly elevated calcium levels and is therefore usually severely symptomatic 4
• Clinical manifestations can range from malaise to lethargy and confusion, constipation, and anorexia 5
• Acute kidney injury is likely the most frequently encountered manifestation of end-organ damage 5
• Diagnosis should include history and physical examination as well as measurement of the above mediators of hypercalcemia 4

Treatment Options

• Treatment aims to decrease serum calcium by increasing calciuresis, decreasing bone resorption, and decreasing intestinal calcium absorption 3
• The mainstays of treatment are IV hydration, bisphosphonates, and calcitonin, denosumab, and in some patients, prednisone, and cinacalcet 4, 3, 6
• Patients with underlying advanced kidney disease and refractory severe hypercalcemia should be evaluated for hemodialysis 4, 3