The following module was designed to supplement medical students’ learning in the clinic. Please take the time to read through each module by clicking the headings below. Information on how to diagnose and manage hypercalcemia.

Hypercalcemia of malignancy is common in advanced stage cancers affecting over 40% of patients (1). Calcium levels require tight regulation and small variations from normal can cause significant morbidity.

Normal physiology of calcium homeostasis

The large majority of the body’s calcium is stored in bone, and a very small amount is in the blood, with about 65% of the blood calcium bound to albumin, unavailable for use (1). Low serum calcium levels stimulate the parathyroid gland to release parathyroid hormone which increases calcium levels in 3 ways: renal tubular reabsorption, vitamin D activation, and mobilization from bone (1). Vitamin D increases calcium absorption from the GI tract and decreases renal excretion (1). On the other side of regulation, calcitonin is a hormone released by parafollicular/C cells in the thyroid gland that is involved in decreasing serum calcium levels by preventing renal reabsorption and calcium mobilization from bone (1).

Pathophysiology of hypercalcemia of malignancy

There are several mechanisms of hypercalcemia of malignancy including humoral hypercalcemia mediated by increased parathyroid hormone-related peptide (PTHrP), local osteolytic hypercalcemia due to breakdown of bone, excess extrarenal activation of activated vitamin D that promotes calcium reabsorption/retention, and excess ectopic or primary PTH secretion (2). The PTHrP mechanism is the most common (80%) and it’s the peptide’s structural similarity to endogenous PTH that drives increased tubular renal absorption of calcium, decreased renal excretion and stimulates osteoblasts to produce RANKL. Local osteolytic hypercalcemia accounts for roughly 20% of hypercalcemia from bone mets and is thought to be due to excessive osteoclast activation and bone resorption due to tumour cytokine secretion (2).

The classic mnemonic for symptoms of hypercalcemia is “stones, bones, abdominal moans, and psychic overtones”. In addition there are characteristic cardiovascular system features of hypercalcemia.

If hypercalcemia is suspected, measuring serum calcium and serum albumin levels (if serum albumin is abnormal, measured calcium needs to be adjusted) is the first step of investigations. Once confirmed, PTH, PTHrP and vitamin D levels will help to characterize the cause of hypercalcemia.

The first step in management is fluid resuscitation with IV normal saline. Patients presenting with hypercalcemia due to bone metastases are usually dehydrated due to hypercalcemia-induced nausea, vomiting, loss of appetite and nephrogenic diabetes insipidus. These factors all contribute to volume depletion and propagate the cycle of further increasing serum calcium (1). In addition to fluids, there are several medications used to reduce serum calcium. Exogenous calcitonin has a fast onset of action and is a good initial therapeutic option while bridging to longer term use therapies (1). It works within 4 hours, but tachyphylaxis often develops around 48 hours which is why it should only be used in the transition period for starting maintenance therapy (2). Bisphosphonates (e.g. zoledronic acid and pamidronate) are used as a longer term therapy, but their calcium lowering effect takes 2-4 days (1). In patients with high levels of PTHrP, bisphosphonates might be less effective and other options such as denosumab may be the next treatment of choice, although this use is off-label (1). Hemodialysis should be considered in patients who cannot be safely rehydrated due to cardiorenal disease.

1. Mirrakhimov AE. Hypercalcemia of Malignancy: An Update on Pathogenesis and Management. N Am J Med Sci [Internet]. 2015 Nov [cited 2019 May 7];7(11):483–93. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26713296
2. Goldner W. Cancer-Related Hypercalcemia. J Oncol Pract [Internet]. 2016 May 21 [cited 2019 May 7];12(5):426–32. Available from: http://ascopubs.org/doi/10.1200/JOP.2016.011155