Hypercalcaemia in Malignancy

The normal range for serum calcium is typically reported as 2.20 to 2.6 mmol.

Hypercalcemia is defined as serum calcium above 2.6. Hypercalcemia occurs in 20-30% of individuals with malignancy. [1]

Calcium Metabolism

Calcium is the most abundant mineral in the body. It is essential for neurotransmission in muscles and nerves, muscle contraction, cardiac function and blood coagulation. There are 25,000 mmol or approximately 1 kg of calcium in the body. More than 90% of the bodys calcium is found in the skeleton.

Calcium enters the body through the small intestine, moves between plasma and intracellular compartments and bone, and is eventually excreted via the kidney. A complex interplay of three major hormones: parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (calcitriol) and calcitonin regulates these processes.

PTH acts to increase plasma calcium levels by:

• Stimulating release of calcium from bone by direct osteolytic action and via osteoclast upregulation;
• Stimulating reabsorption of calcium in the loop of Henle and distal tubule in the kidney;
• Stimulates enzymatic conversion of 25-hydroxyvitamin D to the active metabolite 1,25-dihydroxyvitamin D (calcitriol) in the kidney. The 1,25-dihydroxyvitamin D in turn increases intestinal absorption of calcium.

PTH also acts to decrease serum phosphate levels.

Calcitonin by contrast inhibits the action of osteoclasts, and inhibits renal reabsorption of calcium, in order to decrease plasama calcium levels.

Approximately 40-50% of the calcium in the serum is bound to proteins, primarily albumin, and the remaining calcium is unbound. The unbound portion of calcium in blood is described as free calcium or ionised calcium.

Learning bite

For hypercalcaemia to develop, the normal calcium regulation system must be overwhelmed by an excess of PTH, calcitriol, some other serum factor that can mimic these hormones, or a huge calcium load.

Pathophysiology: Hypercalcaemia of Malignancy

Cancer is the most common cause of hypercalcaemia in inpatients. Several mechanisms can result in hypercalcaemia in malignancy. Hypercalcaemia is often associated with advanced or disseminated malignancy, and therefore carries a poorer prognosis. [2]

1. In humoral hypercalcaemia of malignancy, which is believed to account for around 80% of cases of hypercalcaemia of malignancy, the secretion of Parathyroid Hormone related Peptide (PTHrP) by tumour cells leads to increased release of calcium from bone and increased reabsorption in the kidney. PTHrP secretion is most commonly seen with breast, renal, ovarian and endometrial cancers, as well as Human T-lymphotrophic virus-associated lymphoma and squamous cell carcinomas.

2. Where there is widespread skeletal involvement, osteolysis may lead directly to excessive serum calcium.

3. In calcitriol (1,25-dihydroxyvitamin D)-mediated hypercalcaemia, an overexpression of 1-alpha hydroxylase (the enzyme that converts p25-hydroxyvitamin D to active calcitriol) by malignant or adjacent normal cells may lead to hypercalcium due to an excess of active vitamin D. This is seen most commonly with lymphomas.

4. Rarely, tumours may secrete ectopic PTH.

Signs and Symptoms of Hypercalcaemia

The severity of symptoms is not always related to the degree of hypercalcaemia, but often reflects the rapidity of onset. Patients do not always exhibit all of the clinical features. The onset of hypercalcaemia may be insidious.

Neurological

Fatigue, lethargy, confusion, myopathy, hyporeflexia, seizures, psychosis and coma. The most frequent effect of hypercalcaemia is delirium.

General

Dehydration, polydipsia, polyuria, pruritis. Weakness and bone pain may also be present.

Gastrointestinal

Anorexia, nausea and vomiting, weight loss, constipation, ileus and abdominal pain.

Cardiac

Shortened QT, prolonged PR, Wide and flattened T waves, J waves, Ventricular and Atrial Arrhythmias and Bradycardia which can be fatal

Renal

Polyuria, polydipsia, dehydration and development of kidney stones.

Early

Polyuria, nocturia, polydipsia, dehydration, anorexia, easy fatigability, weakness, hyporeflexia, pain may be precipitated or exacerbated by hypercalcaemia.

Late

Apathy, irritability, depression, decreased ability to concentrate, obtundation, coma, profound muscle weakness, nausea and vomiting, constipation, increased gastric acid secretion, acute pancreatitis, pruritus, visual disturbances, sudden death from cardiac dysrhythmias may occur if calcium rises quickly, especially in patients taking digoxin.

Learning bite

In unexplained vomiting, thirst, polyuria or confusion, it is prudent to check serum calcium.

Physical Examination

Hypercalcaemia has few physical examination findings specific to its diagnosis. Often it is the symptoms or signs of underlying malignancy that bring the patient with hypercalcaemia to seek medical attention.

The primary malignancy may be suggested by lung findings, skin changes, lymphadenopathy, or liver or spleen enlargement.

Hypercalcaemia can produce a number of non-specific findings, as follows:

• Hypertension and bradycardia may be noted in patients with hypercalcaemia
• Abdominal examination may suggest pancreatitis or the possibility of an ulcer
• Patients with long-standing elevation of serum calcium may have proximal muscle weakness that is more prominent in the lower extremities and may have bony tenderness to palpation
• Hyporeflexia and tongue fasciculations may be present
• Anorexia or nausea may occur
• Polyuria and dehydration are common
• Lethargy, stupor or even coma may be observed
• Long-standing hypercalcaemia may cause band keratopathy, but this is rarely recognised in the emergency department

If hypercalcaemia is as a result of sarcoidosis, vitamin D intoxication or hyperthyroidism, patients may have physical examination findings suggestive of those diseases.

Differential Diagnosis of Hypercalcaemia

Non malignant causes of hypercalcaemia include:

• Chronic renal failure
• Endocrine disorders (hyperthyroidism, phaeochromocytoma, Addisons disease)
• Familial hypocalciuric hypercalcaemia
• Immobilisation
• Laboratory artifact due to altered albumin concentration or serum pH
• Medications (vitamin A toxicity [dietary fads, isotretinoin overdose, multivitamin overdose], oestrogens, antioestrogens, thiazides, lithium)
• Milk-alkali syndrome
• Primary hyperparathyroidism
• Vitamin D toxicity
• Granulomatous disease (sarcoidosis, tuberculosis)

Malignancies causing hypercalcaemia

Calcium Level

Determining the Cause

After a diagnosis of hypercalcaemia is established, the next step is to determine the cause. Initial testing is directed at identifying malignancy, hyperparathyroidism and hyperthyroidism, the most common causes of hypercalcaemia.

Measurement of circulating PTH in the serum is the most direct and sensitive measure of parathyroid function. A non-suppressed PTH level in the presence of hypercalcaemia suggests a hyperparathyroidism. If the PTH level is suppressed in the face of an elevated calcium level, hyperparathyroidism is less likely.

Parathyroid hormone-related peptide (PTH-rP) is thought to mediate the hypercalcaemia that develops with many malignancies. Assays to measure this peptide are available.

Other electrolytes also may be disturbed in hypercalcaemia. Serum phosphate levels tend to be low or normal in primary hyperparathyroidism and hypercalcaemia of malignancy. Phosphate levels are elevated in hypercalcaemia secondary to vitamin Drelated disorders or thyrotoxicosis. Serum chloride levels usually are higher than 102 mEq/L in hyperparathyroidism and less than this value in other forms of hypercalcaemia.

If laboratory evidence of primary hyperparathyroidism is present, CT scan of the head, MRI, ultrasound or nuclear parathyroid scans may be helpful.

Plain x-rays may reveal demineralisation, pathologic fractures, bone cysts and bone metastases. Renal imaging, ultrasound or IVP may show evidence of calcification or stones.

Introduction

Patients with mild hypercalcaemia or with moderate hypercalcaemia who are asymptomatic should be monitored, have adequate fluid intake, and receive investigations and treatment for the underlying malignancy. Serial calcium measurement should be undertaken. Urgent treatment should be commenced patients with symptomatic moderate hypercalaemia or severe. [1]

Long term control of hypercalcaemia of hypercalcaemia of malignancy requires treatment of that underlying malignancy. [2] Until this can be achieved, primary treatment goals include:

1. General supportive measures
2. Correcting intravascular volume contraction
3. Enhancing renal excretion of calcium
4. Inhibiting accelerated bone resorption

Management of hypercalcaemia of malignancy may be complex, and it is recommended that clinicians consult local guidelines or the BMJ Best Practice algorithm. [2]

General supportive measures

Important general supportive measures include:

1. Removal of calcium from parenteral feeding solutions and fluids
2. Discontinuation of the use of oral calcium supplements and calcium containing medications, such as antacids
3. Discontinuation of medications that may independently lead to hypercalcaemia e.g. lithium, calcitriol, vitamin D and thiazides
4. Discontinuation of medications that may exacerbate symptoms of hypercalcaemia, such as sedatives and hypnotics.

Further measures can include, if possible, an increase in the weight-bearing mobility of the patient, which theoretically will slow the loss of skeletal calcium associated with immobility, as well as helping to protect the patient from pressure sores, infections, delirium and general deconditioning.

Hydration

Hydration with intravenous crystalloid (typically 0.9% sodium chloride) is the first step in the acute management of hypercalcaemia. Most patients suffering from acute hypercalcaemia are volume contracted. Administration of cystralloid is important because it expands intracellular volume, diluting plasma calcium and increasing renal perfusion and renal calcium clearance. The optimal administration rate of normal saline is determined by the severity of hypercalcaemia, the degree of volume contraction, the ability of the patient to tolerate fluid, and the overall clinical status of the patient. Relatively large volumes of crystalloid may be required: 1-2L as a bolus, and 200-500ml per hour thereafter. [5]

Older Treatments

allium nitrate

Use is now limited as administration is laborious and less effective than previously thought.

Mithramycin

This was the mainstay of therapy for hypercalcaemia associated with cancer before the bisphosphonates became available. It remains effective, but its use is limited by potential adverse effects. [6]

Calcitonin

Calcitonin is not widely available, and its effects are transient, thus limiting its utility. [6] It may be used as an adjunct to other treatments.

Furosemide

Furosemide may be used in fluid overloaded patients, but caution is required as depletion of intravascular sodium and water will result in worsening hypercalcaemia. [2]

Bisphosphonates

Bisphosphonates include zoledronic acid, etidronate disodium and pamidronate disodium. Older first-generation bisphosphonates include clodronate, etidronate and ibandronate.

Bisphosphonates are toxic to osteoclasts and inhibit osteoclast precursors, thereby decreasing osteoclast function. Currently, etidronate is commercially available in both oral and intravenous dosage forms and pamidronate is only available as an intravenous infusion. Pamidronate can be given in day case units and community hospital settings quite easily.

As compared with pamidronate, zoledronate has the advantage of rapid and simpler administration (15 min vs. 2 h for infusion), whereas pamidronate is less expensive [7] (Level 1B).

Pamidronate and zoledronate have been reported to cause or exacerbate renal failure, but this effect has generally occurred in patients receiving multiple doses.

Bisphosphonates have replaced older methods used to treat hypercalcaemia. They are the best studied, safest and most effective agents for use in hypercalcaemia associated with malignancy. They take up to 3 days to start working and 5-7 days to exert maximum effect. Approximately 60-90% of patients have normal serum calcium levels within 4-7 days, and responses last for 1-3 weeks. RCTs of pamidronate have shown it to be effective in reduction of hypercalcaemia associated with malignancy [8,9] (Level 1C). Although a direct comparison of the two drugs in a randomised clinical trial showed a statistically significant increase in the efficacy of zoledronate, the difference in control of calcium was small. [9]

Learning bite

The mainstay of treatment in addition to rehydration has become bisphosphonates.

Glucocorticoids

Steroids such as intravenous dexamethasone may be helpful in treating calcitriol (1,25-dihydroxyvitamin D)-mediated hypercalcaemia. Steroids inhibit calcitriol production by activated mononuclear cells in lung and lymph nodes, thus increasing urinary calcium excretion and decreasing intestinal absorption of calcium. [10]

Denusomab

Denosumab is a monoclonal antibody directed against the receptor activator of nuclear factor- KappaB ligand (RANKL). It reduces osteoclast differentiation and bone resorption. It can be administered subcutaneously. [2]

Denosumab has a lower risk of acute kidney injury than bisphosphonates, and so requires less monitoring, and may be preferred as a first line treatment for hypercalcaemia of malignancy in patients with renal impairment. It may also be used in combination with bisphosphonates. [5]

Potential adverse effects of denosumab include skin infections, acute osteonecrosis of the jaw, and hypocalcaemia in patients with vitamin D deficiency. Rebound hypercalcaemia has been observed in patients taking denosumab. [2]

In June 2018, the UK Medicines and Healthcare products Regulatory Agency (MHRA) issued a safety alert following a pooled analysis of four phase 3 studies of denosumab in patients with advanced malignancies involving bone. [2, 11] New primary malignancies were reported more frequently among patients receiving denosumab than those receiving zoledronic acid (cumulative incidence of new primary malignancy at 1 year was 1.1% for denosumab and 0.6% for zoledronic acid). No treatment-related patterns for individual cancers or cancer groupings were identified. It is not known whether there is an increased risk of new primary malignancy when denosumab is prescribed for the treatment of hypercalcaemia of malignancy. [2]

Dialysis and other Treatments

In patients who have cancers that are likely to respond to therapy, but in whom acute or chronic renal failure is present, aggressive saline infusion is not possible. Further, other therapies such as bisphosphonates should be used with caution, if at all. In these circumstances, dialysis against a dialysate containing little or no calcium may be considered for selected patients. [6] There are no randomised control trials (RCTs) and only case reports [6] (Level 3).

• Moderate symptomatic hypercalcaemia, or severe hypercalcaemia, is a medical emergency requiring immediate treatment.
• Common treatment modalities include general supportive measures, IV hydration, IV bisphosphonates and denusomab.
• Hypercalcaemia in the setting of malignancy usually indicates advanced or disseminated disease and a poorer prognosis.

1. Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. 2005 Jan 27;352(4):373-9.
2. BMJ Best Practice, Hypercalcaemia of Malignancy, 2023.
3. Fraser Health. Hypercalcaemia in malignant disease (palliative management). Hospice Palliative Care, Clinical Practice Committee 2006
4. MDCalc: Calcium Correction for Hypoalbuminaemia and hyperalbuminaemia.
5. El-Hajj Fuleihan G, Clines GA, Hu MI, et al. Treatment of hypercalcemia of malignancy in adults: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2023 Feb 15;108(3):507-28.
6. Kinirons M T. Newer agents for the treatment of malignant hypercalcaemia. Am J Med Sci 1993; 305(6): 403-6
7. Major P Lortholary A Hon J, Zoledronic Acid is superior to pamidronate in the treatment of hypercalcaemia of malignancy: A pooled analysis of 2 randomised controlled clinical trials. Journal Clinical Oncology. 2001; 19: 558-567
8. Nussbaum SR, Younger J, et al., Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: comparison of 30-, 60-, and 90-mg dosages. Am J Med. 1993; 95(3): 297-304.
9. Gucalp R, Ritch P, Wiernik PH, et al. Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia. J Clin Oncol. 1992; 10: 134-42
10. Longmore M, Wilkinson I, et al. Oxford handbook of Clinical Medicine 7th Edition. Oxford University Press 2007; page 138
11. Medicines and Healthcare products Regulatory Agency. Denosumab (Xgeva) for advanced malignancies involving bone: study data show new primary malignancies reported more frequently compared to zoledronate. Jun 2018.