Continuing Education Activity

Hypercalcemia is a common metabolic abnormality observed in both inpatient and outpatient settings. Depending on the serum calcium levels, hypercalcemia is categorized as mild (10–12 mg/dL), moderate (12–14 mg/dL), or severe (>14 mg/dL). Approximately 40% to 45% of serum calcium is bound to albumin, and serum calcium levels may fluctuate with changes in albumin levels. Therefore, ionized or free calcium levels should be measured when hypercalcemia is suspected. The most common cause of malignancy-related hypercalcemia is parathyroid hormone-related peptide (PTHrP). Other common causes include bony metastases and hypervitaminosis D, although rarer causes also exist.

Initial evaluation includes differentiating between benign and malignant causes, with PTH levels aiding in diagnosis. Severe cases require urgent treatment, while management focuses on addressing the underlying malignancy, correcting associated electrolyte imbalances, and patient education on contributing factors. This activity describes the pathophysiology of malignancy-related hypercalcemia and its association with various malignancies. This activity also highlights the importance of collaboration among healthcare providers in the management of this condition.

Objectives:

• Identify the signs and symptoms of malignancy-related hypercalcemia to facilitate early diagnosis and intervention.

• Implement effective management strategies, including the correction of serum calcium levels and treatment of the underlying malignancy.

• Select appropriate treatment modalities based on the severity of hypercalcemia and the underlying malignancy, including pharmacological and supportive care.

• Collaborate with interprofessional healthcare specialists to address the underlying malignancy and tailor treatment plans for hypercalcemia management.

Introduction

Hypercalcemia is a common metabolic abnormality seen in both inpatient and outpatient settings. Depending on the serum calcium levels, hypercalcemia is categorized either as mild (just above normal but <12 mg/dL), moderate (between 12 and 14 mg/dL), or severe (>14 mg/dL).[1] Approximately 40% to 45% of the serum calcium is attached to albumin, and serum calcium levels may fluctuate based on the serum albumin levels. Therefore, the ionized or free calcium levels should be measured when hypercalcemia is suspected for a more accurate assessment.

The corrected calcium could also be calculated using the below formula:

Serum calcium + 0.8 × (4 − patient’s albumin level), where 4.0 g/dL is the normal albumin level.

More than 90% of hypercalcemia cases are caused by primary hyperparathyroidism (PHPT) or malignancy-induced hypercalcemia, with malignancy being the most common cause of hypercalcemia in hospitalized patients.[2][3][4]

Etiology

Hypercalcemia can have multiple causes, with the most common being PHPT, malignancy-induced, medication-induced, familial, or endocrine-related. The initial evaluation of a patient with hypercalcemia requires clinicians to differentiate between benign and malignant causes. PHPT, the most common benign cause, is typically characterized by asymptomatic patients with a long-standing history of mild hypercalcemia.

Serum calcium levels greater than 13 mg/dL upon initial presentation should raise suspicion of malignancy as the cause of hypercalcemia. Symptomatic severe hypercalcemia due to malignancy is associated with a poor prognosis and requires urgent treatment.[5][6][7][8] Additionally, many rare causes of hypercalcemia have been reported in the literature over the years and should be considered once the more common causes have been ruled out.[9][10]

Epidemiology

Hypercalcemia of malignancy occurs in approximately 20% of cancer patients at some point during their clinical course.[11] The most common cancer associated with hypercalcemia is multiple myeloma. A prevalence study reports that hypercalcemia of malignancy is reported in about 2% to 3% of patients diagnosed with cancer, with the incidence gradually decreasing over the years due to improvements in treatment options.[12][13][14]

Pathophysiology

The pathophysiology of hypercalcemia of malignancy is primarily explained through 3 mechanisms—excessive secretion of parathyroid hormone (PTH)-related protein (PTHrP), bony metastases leading to the release of osteoclast-activating factors, and the production of 1,25-dihydroxy vitamin D (calcitriol).[15]

Excessive secretion of PTHrP is the most common cause of hypercalcemia of malignancy, accounting for about 80% of cases.[16][17] This condition is also known as humoral hypercalcemia of malignancy (HHM). This is usually seen in solid tumors and a few cases of non-Hodgkin lymphoma. The most common solid tumors associated with hypercalcemia include squamous cell carcinoma of the head, neck, and lungs, breast cancer, ovarian cancer, renal carcinoma, and certain hematological malignancies, such as leukemia. HHM should be suspected in patients without skeletal metastasis. 

Structurally, PTHrP is similar to PTH in the first 13 amino acid sequences. Due to this structural similarity, PTHrP binds to the same receptor as PTH, leading to bone resorption, increased phosphate excretion from the proximal tubules, and calcium reabsorption from the distal tubules in the kidneys. However, it does not affect the production of 1,25-dihydroxy vitamin D. Laboratory findings typically show elevated PTHrP levels, low to normal PTH levels, and normal 1,25-dihydroxy vitamin D levels. The response to treatment can be monitored by tracking PTHrP levels. Patients with HHM often have advanced disease, which is associated with a poor prognosis.

Bony metastases, which lead to the release of osteoclast-activating factors, account for 20% of hypercalcemia of malignancy cases. They are commonly observed in patients with multiple myeloma and solid tumors, such as breast cancer, that metastasize to the bones. Typical findings include skeletal metastasis with low to low-normal levels of PTH, PTHrP, and 1,25-dihydroxy vitamin D.[14] Although PTHrP levels are low to normal, breast cancer cells in the bone produce PTHrP locally and increase the activity of receptor activator of nuclear factor kappa-B ligand (RANKL), which, in turn, enhances osteoclastic activity and contributes to hypercalcemia.

Almost all cases of Hodgkin lymphoma, about one-third of non-Hodgkin lymphoma cases, and granulomatous diseases such as sarcoidosis and tuberculosis cause hypercalcemia by increasing 1,25-dihydroxy vitamin D production. This subset of patients typically responds well to steroid treatment.

History and Physical

Specific physical examination findings for hypercalcemia are not usually evident, but patients can present with a wide spectrum of symptoms. Depending on the acuity and severity, patients can be asymptomatic or exhibit involvement of multiple organ systems, including the gastrointestinal tract, musculoskeletal system, cardiovascular system (CVS), renal system, and central nervous system (CNS), or experience psychiatric disturbances. In rare cases, band keratopathy may be observed during a slit-lamp examination, indicating calcium phosphate deposits in the cornea.

Renal manifestations range from polyuria, polydipsia, nephrogenic diabetes insipidus, and renal insufficiency to distal renal tubular acidosis secondary to nephrolithiasis. If left untreated, hypercalcemia and hypercalciuria may lead to tubular atrophy, interstitial fibrosis, and renal calcification, resulting in nephrocalcinosis. Gastrointestinal symptoms can vary from anorexia to nausea and constipation. Excessive calcium deposition in the pancreatic duct may lead to pancreatitis. Additionally, hypercalcemia can increase gastrin secretion, contributing to the development of peptic ulcer disease.[18]

Musculoskeletal symptoms may present as muscle weakness and bone pain. Cardiovascular manifestations are subtle, often including short QTc intervals, with rare cases of more severe arrhythmias. Excessive calcium deposition in the heart valves and coronary arteries can increase cardiovascular morbidity. CNS symptoms vary with calcium levels; patients with mild hypercalcemia are often asymptomatic, while those with severe hypercalcemia may experience lethargy, confusion, or even coma, particularly in older populations. Common psychiatric disturbances include anxiety, depression, and cognitive changes.

Evaluation

The initial evaluation of hypercalcemia requires a comprehensive history and physical examination, which can help identify the underlying cause and pathology. Prior laboratory data are valuable, providing insights into baseline calcium levels and the duration of hypercalcemia. Medication history, including prescription drugs, over-the-counter vitamins, and supplements, along with dietary history, family history, and any history of granulomatous disease, should be systematically reviewed. Initial labs should include PTH levels, as this helps differentiate between PTH-related hypercalcemia and non-PTH–mediated hypercalcemia. PTH-related hypercalcemia is seen in conditions such as PHPT and familial hyperparathyroid syndromes, while non-PTH–related hypercalcemia occurs in malignancies, granulomatous diseases, endocrine disorders, and vitamin D intoxication.[19]

Familial hypocalciuric hypercalcemia syndrome should be suspected in patients with minimally elevated PTH levels and low urinary calcium excretion on a 24-hour urinary calcium. Low-normal or low levels of PTH (<20 pg/mL) should raise suspicion of non-PTH–related causes. In such cases, PTHrP and vitamin D metabolites, including 25-hydroxyvitamin D and 1,25-dihydroxy vitamin D levels, should be checked.

If PTHrP is elevated, it indicates HHM. Vitamin D intoxication leads to elevated 25-hydroxyvitamin D levels. Elevated 1,25-dihydroxy vitamin D levels suggest lymphoma or granulomatous diseases. Serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP) with immunofixation, and serum-free light chains should be evaluated to rule out multiple myeloma if vitamin D levels are within the normal range. In patients with malignancy-induced hypercalcemia, PTH levels should still be assessed to identify potential coexisting PHPT. 

Treatment / Management

Treatment should be tailored to reduce serum calcium levels, address the patient's symptoms, and target the underlying cause. Serum phosphorus levels should be monitored and repleted, as hypophosphatemia often accompanies hypercalcemia, complicating its treatment. Asymptomatic patients with mild to moderate hypercalcemia do not require immediate therapy, but managing the underlying cause is essential. Patients should be educated on diet and medications, as well as the importance of avoiding dehydration and physical inactivity. Symptomatic patients with severe hypercalcemia require urgent treatment.[20][21][22]

Initial treatment involves intravenous (IV) normal saline, along with calcitonin and bisphosphonates. Normal saline acts immediately, with its effects lasting until the fluids are discontinued. Calcitonin takes effect within 4 to 6 hours and lasts for about 2 days, while bisphosphonates begin working in 2 to 3 days, with effects lasting for 2 to 4 weeks. This approach aims to lower serum calcium levels and maintain them within normal limits as long as possible while the underlying cause is being identified and treated.[23][24][25]

IV hydration with normal saline at a rate of 200 to 300 mL/h is administered to maintain an adequate urine output of more than 100 mL/h, helping restore intravascular volume and increase urinary calcium excretion. Caution should be exercised when administering IV fluids to patients with heart or renal failure. Loop diuretics, which promote urinary calcium excretion by inhibiting calcium reabsorption at the loop of Henle, should only be administered after adequate IV resuscitation is achieved.

Calcitonin should be administered at a dose of 4 IU/kg alongside normal saline infusion to help prevent bone resorption and increase urinary calcium excretion. Calcitonin is a very fast-acting medication, but its effects are limited in duration.[26]

Bisphosphonates, such as zoledronic acid (4 mg IV over 15-30 minutes) or pamidronate (60-90 mg IV over 2 hours), are recommended for patients without kidney dysfunction. Zoledronic acid is preferred for hypercalcemia secondary to malignancy due to its greater potency and shorter infusion time.[27] Bisphosphonates are also commonly used in patients with bone metastases to prevent skeletal complications. The main adverse effects of bisphosphonates include osteonecrosis of the jaw and nephrotoxicity.

Denosumab works by inhibiting RANKL and was previously considered only for patients who did not respond to zoledronic acid or those with kidney impairment, as it is not cleared by the kidneys.[28][29] However, the latest guidelines from the Endocrine Society now recommend using denosumab early, as it has shown strong efficacy in lowering calcium levels and reducing recurrent episodes of hypercalcemia.[22][30] Denosumab is also administered regularly to cancer patients, even those without hypercalcemia, primarily for the prevention of bone complications.[30][14]

Glucocorticoid therapy should be considered for patients with increased 1,25-dihydroxy vitamin D production, such as those with lymphoma or granulomatous diseases, as it reduces vitamin D production and decreases calcium absorption from the intestines.

Calcimimetic agents, such as cinacalcet, are preferred for hemodialysis patients and those with hypercalcemia due to parathyroid cancer.[31][32][33]

If all other strategies fail, hemodialysis is used to treat hypercalcemia. Hemodialysis should also be considered for patients with severe heart or renal failure who cannot tolerate adequate IV hydration.[34]

Differential Diagnosis

The following conditions should be considered when evaluating hypercalcemia:

• Adrenal insufficiency
• Berylliosis
• Coccidioidomycosis
• Crohn disease
• Hyperkalemia
• Hypermagnesemia
• Hypernatremia
• Hyperparathyroidism
• Hyperphosphatemia
• Hyperthyroidism 
• Milk-alkali syndrome
• Vitamin D toxicity

Prognosis

The prognosis of malignancy-related hypercalcemia depends on the underlying cause and the type of cancer responsible. Early stages of the disease typically have a more favorable prognosis compared to more advanced stages. Late diagnosis often correlates with a poorer prognosis. Elevated levels of 1,25-dihydroxy vitamin D have been shown to be associated with recurrent hypercalcemia and a more severe prognosis.[35]

Complications

Hypercalcemia, if undiagnosed or inadequately treated, can lead to severe complications such as kidney failure and bone issues, including decreased bone density, osteoporosis, and fractures.

Deterrence and Patient Education

Patients with calcium abnormalities related to underlying cancer should follow up with an endocrinologist in addition to receiving mandatory oncology evaluation and treatment. If complications arise in other organ systems, patients are encouraged to consult specialists in the affected areas, such as cardiology, ophthalmology, neurology, or neurosurgery.

Pearls and Other Issues

Key facts to keep in mind regarding malignancy-related hypercalcemia include:

• Malignancy is the most common cause of hypercalcemia in hospitalized patients.
• The pathophysiology of hypercalcemia of malignancy involves 3 main mechanisms—excessive secretion of PTHrP, bony metastases with the release of osteoclast-activating factors, and the production of 1,25-dihydroxy vitamin D (calcitriol).
• PTHrP, also known as HHM, is the most common causative factor.
• The most common solid tumors associated with hypercalcemia include squamous cell carcinoma of the head, neck, and lungs, breast cancer, ovarian cancer, renal carcinoma, and some hematological malignancies such as leukemia. HHM should be suspected in patients without any skeletal metastasis. 
• IV hydration with normal saline as the foundation of therapy.
• Other treatment options include zoledronic acid, pamidronate, and denosumab. 
• Steroids are preferred with the presence of hypervitaminosis D.
• Cinacalcet is preferred for hemodialysis patients and those with parathyroid cancer.

Enhancing Healthcare Team Outcomes

Malignancy-associated hypercalcemia is best managed by an interprofessional healthcare team, including an oncologist, internist, endocrinologist, and surgeon, who guides treatment. Pain specialists should also be involved, as many patients may present with varying degrees of pain. Over 90% of hypercalcemia cases are caused by PHPT and malignancy-induced hypercalcemia. Nurses, laboratory personnel, and pharmacists are integral members of the interprofessional healthcare team, contributing to comprehensive care and improved patient outcomes.

Nursing staff have a key role in case management by assisting with patient assessment, providing counseling, and serving as a liaison between the different specialties. Pharmacists ensure the appropriate medications are administered at the correct doses, monitor for potential drug interactions, and counsel patients on possible adverse effects. Laboratory technicians ensure blood collection is completed and serum values are processed and reported to clinicians promptly. All interprofessional healthcare team members must maintain accurate records, ensuring everyone involved in the patient's care can access the same data. This collaborative approach optimizes patient outcomes.

Malignancy is the most common cause of hypercalcemia in hospitalized patients. Although most cases are managed on an outpatient basis, severe hypercalcemia often requires inpatient treatment. The prognosis depends on the stage of the primary malignancy and the severity of the hypercalcemia. Patients with uncontrolled malignancy and severe hypercalcemia typically have a poor prognosis.