What is the significance of mild hypercalcemia (elevated calcium levels) in initial investigations?

From the Guidelines

The initial investigation for mild raised calcium should begin with a repeat calcium measurement along with albumin levels to calculate corrected calcium, as protein binding affects total calcium readings. This step is crucial in confirming the presence of hypercalcemia and ruling out any laboratory errors. If hypercalcemia is confirmed, measuring parathyroid hormone (PTH) levels is essential, as it helps distinguish between PTH-dependent causes (like primary hyperparathyroidism) and PTH-independent causes (like malignancy) 1. Additional first-line tests should include renal function (creatinine, BUN), 25-hydroxyvitamin D, phosphate, and alkaline phosphatase. A complete medication review is also vital, as certain medications such as thiazide diuretics, lithium, and excessive vitamin D or calcium supplements can cause hypercalcemia 1.

Some key points to consider in the investigation of mild raised calcium include:

• The potential harm associated with a positive calcium balance in some cases, particularly in patients with chronic kidney disease (CKD) 1
• The increased prevalence of hypocalcemia after the introduction of calcimimetics (cinacalcet) in patients receiving dialysis 1
• The association between higher calcium concentrations and increased mortality in adults with CKD, as well as the link between higher serum calcium concentrations and nonfatal cardiovascular events 1

A thorough history and physical examination focusing on symptoms like fatigue, bone pain, abdominal discomfort, and cognitive changes is also important. If primary hyperparathyroidism is suspected (elevated PTH with hypercalcemia), consider neck ultrasound to evaluate for parathyroid adenoma. For PTH-independent hypercalcemia with concerning features, check for malignancy markers and consider chest X-ray, mammography, or age-appropriate cancer screening. This systematic approach helps identify the underlying cause of mild hypercalcemia, which is most commonly primary hyperparathyroidism or malignancy in adults.

From the FDA Drug Label

At baseline the mean (SE) serum calcium was 14.1 (0.4) mg/dL. At the end of the titration phase, the mean (SE) serum calcium was 12.4 (0.5) mg/dL, which is a mean reduction of 1. 7 (0. 6) mg/dL from baseline. At baseline the mean (SE) serum calcium was 12.7 (0.2) mg/dL. At the end of the titration phase the mean (SE) serum calcium was 10.4 (0.3) mg/dL, which is a mean reduction of 2. 3 (0. 3) mg/dL from baseline.

The initial investigation of mild raised calcium may involve the use of cinacalcet to reduce serum calcium levels.

• Key findings:
  • Cinacalcet reduced mean serum calcium levels from 14.1 mg/dL to 12.4 mg/dL in patients with parathyroid carcinoma.
  • Cinacalcet reduced mean serum calcium levels from 12.7 mg/dL to 10.4 mg/dL in patients with severe hypercalcemia due to primary hyperparathyroidism.
• Clinical decision: Cinacalcet may be considered for the treatment of mild raised calcium, but the dosage and efficacy should be closely monitored 2.

From the Research

Initial Investigation of Mild Raised Calcium

• Mild hypercalcemia is usually asymptomatic but may be associated with constitutional symptoms such as fatigue and constipation in approximately 20% of people 3
• The most important initial test to evaluate hypercalcemia is serum intact parathyroid hormone (PTH), which distinguishes PTH-dependent from PTH-independent causes 3
• An elevated or normal PTH concentration is consistent with primary hyperparathyroidism (PHPT), while a suppressed PTH level indicates another cause 3

Causes of Hypercalcemia

• Approximately 90% of people with hypercalcemia have primary hyperparathyroidism (PHPT) or malignancy 3
• Additional causes of hypercalcemia include granulomatous disease, endocrinopathies, immobilization, genetic disorders, and medications such as thiazide diuretics and supplements such as calcium, vitamin D, or vitamin A 3

Management of Mild Hypercalcemia

• Mild hypercalcemia usually does not need acute intervention 3
• If due to PHPT, parathyroidectomy may be considered depending on age, serum calcium level, and kidney or skeletal involvement 3, 4, 5, 6, 7
• In patients older than 50 years with serum calcium levels less than 1 mg above the upper normal limit and no evidence of skeletal or kidney disease, observation may be appropriate 3

Medical Management of Primary Hyperparathyroidism

• Medical management may be considered in those with mild asymptomatic disease, contraindications to surgery, or failed previous surgical intervention 4, 7
• Calcium and vitamin D intake should be optimized, and antiresorptive therapy may be used for skeletal protection in patients with an increased fracture risk 4, 7
• Cinacalcet, a calcimimetic agent, has been shown to effectively lower serum calcium and PTH levels 4