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Malignancy-Related Hypercalcemia
Anusha Vakiti; Prerna Mewawalla.

Author Information
Last Update: July 25, 2021.

Continuing Education Activity

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 when levels
are between 10 to 12 mg/dL, moderate when levels are between 12 to 14 mg/dL, or severe when
levels are more than 14 mg/dL. 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,
ionized or free calcium levels should be measured when hypercalcemia is suspected. This
activity describes the pathophysiology of malignancy related hypercalcemia and highlights the
role of the interprofessional team in its management.

Objectives:

Identify the etiology malignancy related hypercalcemia.

Review the presentation of a patient with malignancy related hypercalcemia.

Outline the treatment and management options available for malignancy related
hypercalcemia.

Describe some interprofessional team strategies for improving care and outcomes in
patients with malignancy related hypercalcemia.

Access free multiple choice questions on this topic.

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 when levels
are between 10 to 12 mg/dL, moderate when levels are between 12 to 14 mg/dL, or severe when
levels are more than 14 mg/dL. 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,
ionized or free calcium levels should be measured when hypercalcemia is suspected. The
corrected calcium can be calculated by using the following formula: serum calcium + 0.8 x (4-
patient’s albumin level); 4 is normal albumin level in g/dL. More than 90% of the cases of
hypercalcemia are due to primary hyperparathyroidism and malignancy-induced hypercalcemia.
Malignancy remains the most common cause of hypercalcemia in hospitalized patients.[1][2][3]

Etiology
There are multiple causes of hypercalcemia. The most common ones are primary
hyperparathyroidism (PHPT), malignancy-induced, medication-induced, familial, or endocrine-
related. The initial evaluation of a patient with hypercalcemia requires a clinician to differentiate
between the benign and malignant causes. The most common benign cause is PHPT, and patients
are usually asymptomatic and have a long-standing history of mild hypercalcemia. Serum
calcium levels greater than 13 mg/dL on initial presentation should raise suspicion for
malignancy as the cause of hypercalcemia. Symptomatic severe hypercalcemia due to
malignancy portends a poor prognosis and requires emergent treatment.[4][5][6]
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Epidemiology
Hypercalcemia of malignancy occurs in approximately 20% of all cancer patients during their
clinical course. The most common cancer associated with hypercalcemia of malignancy is
multiple myeloma which has the highest prevalence of hypercalcemia of malignancy. Based on a
prevalence study, hypercalcemia of malignancy in the United States in 2013 was 71,744 and has
been gradually decreasing over the years.

Pathophysiology
The pathophysiology of hypercalcemia of malignancy is mainly through three mechanisms:
excessive secretion of parathyroid hormone-related protein (PTHrP), bony metastasis with the
release of osteoclast activating factors, and production of 1,25-dihydroxy vitamin D (calcitriol).

Excessive secretion of PTHrP is the most common cause of hypercalcemia of malignancy. It is

also known as humoral hypercalcemia of malignancy (HHM) and accounts for about 80% of the
cases. It is usually seen in solid tumors and few cases of non-Hodgkin lymphoma. The common
solid tumors include squamous cell carcinoma of the head, neck, and lungs, breast cancer,
ovarian cancers, renal carcinoma, and few hematological malignancies like leukemia. HHM
should be suspected in patients without any skeletal metastasis. Structurally, PTHrP is similar
to parathyroid hormone (PTH) in the first 13 amino acid sequences. Due to the similarity in
structure, it acts at the same receptor as PTH and causes bone resorption, increased phosphate
excretion from the proximal tubules, and calcium reabsorption from the distal tubules. It does not
have any effect on 1,25-dihydroxy vitamin D production. Lab findings are consistent with
elevated PTHrP, low to normal PTH, and 1,25-dihydroxy vitamin D levels. Response to
treatment can be evaluated by monitoring the levels of PTHrP. Usually, patients with HHM tend
to have advanced disease, and it portends a poor prognosis.

Bony metastasis causing the release of osteoclast activating factors contribute to 20% of the
cases and are commonly seen in patients with multiple myeloma and solid organ tumors which
metastasize to bones such as breast cancer. Common findings include skeletal metastasis with
low to low-normal PTH, PTHrP, and 1,25-dihydroxy vitamin D levels. Though the levels of
PTHrP 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, promotes
osteoclastic activity and hypercalcemia.

Almost all cases of Hodgkin lymphoma and about one-third of non-Hodgkin lymphoma cases
and granulomatous diseases like sarcoidosis and tuberculosis cause hypercalcemia by increasing
1,25-dihydroxy vitamin D production. This subset of the population responds well to steroids.

History and Physical

No specific physical examination findings indicate hypercalcemia. However, patients can present
with a wide spectrum of symptoms. Depending on the acuity and severity, patients can either be
asymptomatic or can have involvement of multiple organ systems such as gastrointestinal tract
(GI), musculoskeletal system, cardiovascular system (CVS), renal involvement, and central
nervous system (CNS)or psychiatric disturbances.

The renal manifestations can vary from polyuria, polydipsia, nephrogenic diabetes insipidus,
renal insufficiency, distal renal tubular acidosis (RTA) secondary to nephrolithiasis. If left
untreated, hypercalcemia and hypercalciuria can lead to tubular atrophy, interstitial fibrosis, and
calcification and cause nephrocalcinosis. GI symptoms can vary from anorexia, nausea, and
constipation. Excessive calcium deposition in the pancreatic duct can cause pancreatitis.
Hypercalcemia also enhances secretion of gastrin levels, which can contribute to peptic ulcer
disease. Musculoskeletal symptoms can manifest as muscle weakness and bone pain. CVS
manifestations are subtle and include short QTc interval and, rarely, arrhythmias. Excess calcium

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can deposit in the heart valves and the coronaries and increase cardiovascular morbidity. CNS
symptoms depend on the levels. Mild cases are asymptomatic. Severe hypercalcemia can cause
lethargy, confusion, and coma, which is commonly seen in the elderly population. Common
psychiatric disturbances include anxiety, depression, or cognitive disturbances.

Evaluation
The initial evaluation of hypercalcemia mandates a thorough history and physical, as it can
prompt the clinician to the underlying cause and pathology. Prior laboratory data is significant
and can give clues about the baseline calcium levels and duration of hypercalcemia. Medication
history (prescription, OTC, supplements), dietary history, family history, and any evidence of
prior granulomatous disease need to be reviewed systematically. Initial labs to be checked
include PTH levels, as this can differentiate between PTH related hypercalcemia and non-PTH
related hypercalcemia. Hypercalcemia secondary to PTH is seen in primary hyperparathyroidism
and familial hyperparathyroid syndromes, whereas non-PTH related hypercalcemia is seen in
malignancies, granulomatous diseases, and vitamin D intoxication. Familial hypocalciuric
hypercalcemia (FHH) should be suspected in patients with minimally elevated PTH levels and
low urinary calcium excretion on 24-hour urinary calcium. Low-normal or low levels of PTH
(less than 20 pg/mL) should raise the suspicion of non-PTH-related causes and PTHrP, and
vitamin D metabolites such as 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels should
be checked. If PTHrP is elevated, it signifies HHM. Vitamin D intoxication causes elevated 25-
hydroxy vitamin D levels. Lymphoma and granulomatous diseases are suspected when 1,25-
dihydroxy vitamin D levels are elevated. Serum electrophoresis (SPEP), urine electrophoresis
(UPEP) with immunofixation, and serum-free light chains are to be checked to rule out multiple
myeloma if the vitamin D levels are in normal range. In patients with malignancy-induced
hypercalcemia, PTH levels also should be checked, as there is a higher incidence of coexisting
PHPT. Very rarely, band keratopathy can be seen via slit lamp examination, which signifies
calcium phosphate deposits in the cornea.

Treatment / Management
Treatment should be tailored to lower the serum calcium levels to treat the patient’s symptoms
and target the underlying cause. Serum phosphorus levels need to be monitored and replaced, as
hypophosphatemia is usually associated with hypercalcemia and increases the difficulty in
treating hypercalcemia. If the patient is not symptomatic, mild and moderate hypercalcemia does
not require immediate therapy and management of the underlying cause is required. Patients
should be educated about diet, medications, and avoiding dehydration and physical inactivity.
Symptomatic patients with severe hypercalcemia need emergent treatment. Initial treatment
includes intravenous (IV) normal saline (NS) along with calcitonin and bisphosphonates. NS acts
immediately, and its effect lasts until the fluids are discontinued. Calcitonin acts within 4 to 6
hours and lasts for about 2 days, whereas bisphosphonates exhibit their action in 2 to 3 days and
their effect lasts for 2 to 4 weeks. This approach is tailored to lower the serum calcium levels and
maintain them.[7][8][9][8]

IV hydration with NS at the rate of 200 to 300 mL/hr is given to maintain adequate urine output
of more than 100 mL/hr, thus restoring intravascular volume and increasing urinary calcium
excretion. IV hydration is to be given cautiously to patients with heart or renal failure. Loop
diuretics, which help in promoting urinary calcium excretion by inhibiting reabsorption of
calcium at the Loop of Henle, are given only after adequate IV resuscitation. Calcitonin (4
international units/kg) should be administered along with NS infusion to help prevent bone
resorption and increase urinary calcium excretion. It is a very fast acting medication, but its
effect is limited. Bisphosphonates, such as zoledronic acid (ZA) (4mg IV over 15 minutes) or
pamidronate (60 to 90 mg IV over 2 hours), are also given. ZA is preferred in hypercalcemia
secondary to malignancy as it is more potent and can be given over a shorter course of time.

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Bisphosphonates are also given in patients with bone metastasis to prevent any skeletal
complications. The main side effects include osteonecrosis of the jaw and nephrotoxicity.

Denosumab acts by inhibiting the RANKL, and it should be considered when there is no
response to zoledronic acid. Glucocorticoids are considered in patients with increased 1,25-
dihydroxy vitamin D production, such as lymphomas or granulomatous diseases, as they
decrease vitamin D production as well as calcium absorption from the intestines. Calcimimetics,
such as Cinacalcet, is preferred in hemodialysis patients and hypercalcemia secondary to
parathyroid cancer. If these strategies fail, then hemodialysis is done to treat the hypercalcemia.
It is also considered in patients with severe heart or renal failure who cannot tolerate adequate IV
hydration.

Differential Diagnosis

Adrenal insufficiency

Berylliosis

Coccidioidomycosis

Crohn’s disease

Hyperkalemia

Hypermagnesemia

Hypernatremia

Hyperparathyroidism

Hyperphosphatemia

Hyperthyroidism

Enhancing Healthcare Team Outcomes

Malignancy-associated hypercalcemia is ideally treated by an interprofessional team that consists
of an oncologist, internist, endocrinologist, and a surgeon. It is also important to involve a pain
specialist because many patients also have varying degrees of pain. More than 90% of the cases
of hypercalcemia are due to primary hyperparathyroidism and malignancy-induced
hypercalcemia. Malignancy remains the most common cause of hypercalcemia in hospitalized
patients. While most cases are managed as outpatients, severe hypercalcemia requires in-patient
treatment. The outcome depends on the stage of the primary malignancy and severity of
hypercalcemia. Patients with uncontrolled malignancy and severe hypercalcemia have a poor
prognosis. 

Review Questions

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References
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