What is the workup for hypercalcemia and elevated alkaline phosphatase (ALP) levels?

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Last updated: March 6, 2025 • View editorial policy

From the FDA Drug Label

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From the Research

The workup for hypercalcemia with elevated alkaline phosphatase should begin with confirming the hypercalcemia through repeat testing of serum calcium, ionized calcium, and albumin (to calculate corrected calcium), followed by ordering parathyroid hormone (PTH) levels to differentiate between PTH-dependent and PTH-independent causes, as recommended by the most recent study 1. The initial step in evaluating hypercalcemia is to confirm the diagnosis through repeat testing, as mild hypercalcemia may be asymptomatic but can still have significant underlying causes. Once confirmed, PTH levels are crucial in differentiating between primary hyperparathyroidism (PHPT) and other causes of hypercalcemia, such as malignancy.

  • For patients with elevated alkaline phosphatase, which suggests bone involvement, additional tests should include: + 25-hydroxyvitamin D + Phosphorus + Complete blood count + Comprehensive metabolic panel + Urinary calcium excretion
  • Imaging studies are essential, including: + Bone scan or skeletal survey to identify bone lesions + Neck ultrasound if hyperparathyroidism is suspected
  • Consider serum protein electrophoresis and urine protein electrophoresis to rule out multiple myeloma, and chest X-ray to screen for malignancy. Specific markers like PTH-related protein should be measured if malignancy is suspected, as supported by studies 2, 3. This comprehensive approach helps identify the underlying cause, which commonly includes primary hyperparathyroidism, malignancy, Paget's disease, or metastatic bone disease. The combination of hypercalcemia with elevated alkaline phosphatase often points to increased bone turnover, making bone-related pathologies particularly important to investigate. Treatment should be directed at the underlying cause while managing acute hypercalcemia with hydration, loop diuretics, and bisphosphonates if severe, with denosumab being a potential option for severe hypercalcemia due to primary hyperparathyroidism when immediate surgery is not feasible, as demonstrated in a recent study 4. The management of hypercalcemia involves addressing the underlying cause, whether it be PHPT, malignancy, or another condition. For severe hypercalcemia, immediate intervention with hydration and bisphosphonates is critical, with denosumab offering an alternative for specific cases. The choice of treatment should be guided by the severity of hypercalcemia, the presence of symptoms, and the underlying cause, with the goal of improving morbidity, mortality, and quality of life.

References

Research

Hypercalcemia: A Review.

JAMA, 2022

Research

Hypercalcemia: an evidence-based approach to clinical cases.

Iranian journal of kidney diseases, 2009

Research

Treatment of chronic hypercalcemia.

Medicinal chemistry (Shariqah (United Arab Emirates)), 2012

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This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.