What is the cause of hypercalcemia with normal Parathyroid Hormone (PTH) levels?

From the Guidelines

Hypercalcemia with normal Parathyroid Hormone (PTH) levels is most likely caused by non-parathyroid factors, and malignancy is a leading etiology, particularly through production of parathyroid hormone-related protein (PTHrP) or bone metastases. The diagnosis and management of hypercalcemia in patients with chronic kidney disease-mineral and bone disorder (CKD-MBD) have been updated in the 2017 clinical practice guideline, which emphasizes the importance of avoiding inappropriate calcium loading in adults with CKD 1.

Key Considerations

• Malignancy, vitamin D toxicity, granulomatous diseases, medications, hyperthyroidism, and milk-alkali syndrome are potential causes of hypercalcemia with normal PTH levels.
• Initial management involves hydration with normal saline to promote calcium excretion, followed by loop diuretics like furosemide after adequate hydration.
• For severe hypercalcemia, bisphosphonates such as zoledronic acid or pamidronate are effective, while calcitonin can provide rapid but temporary relief.
• Denosumab may be used in renal impairment when bisphosphonates are contraindicated.

Diagnostic Approach

• Identifying and addressing the underlying cause is crucial, and a thorough workup including PTHrP levels, vitamin D metabolites, chest imaging, and malignancy screening is necessary.
• The 2017 clinical practice guideline update highlights the importance of serial assessments of biochemical variables, including serum phosphate, calcium, and PTH, in patients with CKD-MBD 1.
• Treatment approaches should focus on patients with overt hyperphosphatemia, and the use of calcium-based phosphate binders should be restricted in patients with hyperphosphatemia across the CKD spectrum.

Management Priorities

• Avoiding inappropriate calcium loading in adults with CKD is a key recommendation, and treatment should focus on promoting bone accrual and reducing arterial calcification 1.
• The choice of phosphate binders, such as calcium-containing or calcium-free options, should be based on individual patient needs and the potential risks and benefits of each treatment approach.

From the FDA Drug Label

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.

Humoral hypercalcemia usually occurs in squamous cell malignancies of the lung or head and neck or in genitourinary tumors such as renal cell carcinoma or ovarian cancer Skeletal metastases may be absent or minimal in these patients.

Extensive invasion of bone by tumor cells can also result in hypercalcemia due to local tumor products that stimulate bone resorption by osteoclasts.

Tumors commonly associated with locally mediated hypercalcemia include breast cancer and multiple myeloma

The cause of hypercalcemia with normal Parathyroid Hormone (PTH) levels is likely due to malignancy-related hypercalcemia, which can be divided into two groups:

• Humoral hypercalcemia: caused by factors such as parathyroid hormone-related protein (PTH-rP) produced by the tumor, which stimulates osteoclast activity and bone resorption.
• Hypercalcemia due to tumor invasion of bone: caused by local tumor products that stimulate bone resorption by osteoclasts. This is supported by studies 2 and 2.

From the Research

Causes of Hypercalcemia with Normal Parathyroid Hormone (PTH) Levels

• Hypercalcemia can be caused by various factors, including non-parathyroid conditions such as ingestion of certain medications, excessive vitamin A intake, endocrinopathies, abnormal nutrient intake, and prolonged immobilization 3
• Neoplasia is the most common cause of nonparathyroid hypercalcemia, often due to the secretion of parathyroid hormone-related peptide (PTHrP) by solid tumors or hematologic tumors 3
• Other humoral factors, such as 1,25-dihydroxyvitamin D, can also contribute to hypercalcemia, particularly in cases of lymphomas or benign granulomatous disorders 3
• Vitamin D intoxication can cause hypercalcemia due to overproduction of 25-hydroxyvitamin D, even in the absence of conversion to 1,25-dihydroxyvitamin D 3
• Malignancies metastatic to bone or arising in bone, such as multiple myeloma, can produce growth factors and cytokines that contribute to osteolysis and hypercalcemia 3

Specific Conditions Associated with Hypercalcemia and Normal PTH Levels

• Primary hyperparathyroidism can present with hypercalcemia and undetectable PTH levels, as seen in a case report where a patient had a parathyroid adenoma and undetectable PTH levels, which became detectable after parathyroidectomy 4
• Parathyroid carcinoma can cause refractory hypercalcemia, which may be managed with denosumab, a monoclonal antibody that inhibits osteoclast formation and activity 5

Diagnostic Considerations

• A comprehensive workup, including laboratory and imaging tests, is necessary to exclude common non-parathyroid causes of hypercalcemia and to identify the underlying cause of hypercalcemia with normal PTH levels 4
• Genetic mutations, such as those affecting the PTH gene or the calcium-sensing receptor (CASR) gene, can contribute to hypercalcemia and may be identified through genetic testing 6, 4