Hypercalcaemia of malignancy refers to a metabolic state where corrected calcium levels are abnormally elevated, owing to either local osteolysis or humoral factors in the presence of a tumour.
The symptom profile that manifests can be particularly unpleasant, and so recognition and treatment of this metabolic aberration is critical for patient well-being.
In this article, we shall consider the pathophysiology, clinical presentation and approach to assessment and management for hypercalcaemia of malignancy.
Calcium is a cation with a charge of 2+ and has several important functions:
- Present in the hydroxyapatite, Ca5(PO4)3(OH), the mineral within bones supporting their structure
- Acts as an intracellular stimulus for neurotransmitter release and muscle contraction
- Facilitates the co-location of coagulation factors at the platelet membrane
- Critical for several intra-cellular second messenger signalling systems
Within the serum, calcium exists in two forms: (i) Free ionised – this is the active form (Ca2+), and (ii) Bound to albumin – this is the inactive form. The two together give the “total calcium”. When measuring serum calcium levels for clinical purposes, the albumin level must be taken into account and hence, clinicians will request a “corrected calcium”.
Regulation of Serum Calcium levels
This is a complex endocrine axis with several organs and hormones at play. Briefly, it consists of:
- Parathyroid gland – this secretes parathyroid hormone (PTH) in response to low Ca2+ levels and acts on the kidneys to increase Vitamin D activation.
- Kidneys and GI tract – the proximal tubular cells within the nephron synthesise and express the enzyme 1-α-hydroxylase, which completes the activation of Vitamin D, which subsequently acts on the GI tract to increase calcium reabsorption.
- Thyroid gland – parafollicular cells secrete calcitonin in the presence of high Ca2+ levels, which promotes deposition of Ca2+ into the bones.
High Ca2+ → release of calcitonin → Ca2+ deposition in bones + ↓ reabsorption at kidneys
Low Ca2+ → PTH release → ↑ bone resorption + ↑ reabsorption at kidneys, (also, ↑ activation of vitamin D leads to ↑ GI absorption of calcium)
Mechanisms of Hypercalcaemia in Malignancy
For hypercalcaemia to develop, tumours either: (i) Release humoral factors which disturb the endocrine regulation of Ca2+ levels, or (ii) Release cytokines/chemokines which promote local osteolysis.
Both the release of PTH related peptide, or PTHrp, and calcitriol (activated vitamin D), can result in hypercalcaemia of malignancy.
At the molecular level, the degree of osteoclast activity is determined by a triad of factors:
- Receptor-activator of nuclear factor kappa-beta (RANK) – this receptor is present on the surface of osteoclast precursors.
- RANK-ligand – this is an osteoclast-activating factor which binds to RANK and stimulates the differentiation of precursors, as well as the activation and fusion of mature osteoclasts, to form a functional multinucleated osteoclast which is capable of bone resorption.
- Osteoprotegrin (OPG) – this is a “decoy” receptor which competes with RANK for the binding of RANK-ligand, thus acting as an inhibitory molecule for the activation of osteoclasts.
Tumour cells alter the balance between OPG, RANK and RANK-ligand, such that there is a net increase in osteoclast activity, which is unbalanced by osteoblastic activity, resulting in bone resorption. This balance shift is achieved either by:
- Direct secretion of RANK-ligand
- Stimulation of RANK-ligand secretion by bone stromal cells
- Inhibition of OPG secretion
Tumours which result in osteolytic hypercalcaemia include multiple myeloma, prostate, breast, renal, lung and thyroid cancers.
The presentation of hypercalcaemia can be incredibly diverse, and examples of symptoms and signs are shown in Table 1.
|General||Polydipsia, polyuria, pruritis||Dehydration – sunken eyes, reduced skin turgor, dry mucous membranes, tachycardia, hypotension|
|Gastrointestinal||Nausea, vomiting, constipation
|Ileus, weight loss, pancreatitis, peptic ulceration|
|Neurological||Fatigue, confusion, psychosis||Myopathy, hyporeflexia, seizures, coma|
|Cardiac||Palpitations||Bradycardia, a range of dysrhythmias, a range of ECG findings|
Table 1 – The variety of symptoms and signs associated with hypercalcaemia.
A common memory aid for the presentation of hypercalcaemia is as follows:
- Bones – hypercalcaemia, bone pain
- Groans – nausea and vomiting
- Thrones – time spent on the toilet either due to polyuria or constipation
- Stones – renal stones made of calcium phosphate
- Psychic moans – confusion or psychosis
Approach to Assessment
Whilst hypercalcaemia is often the consequence of an underlying cancer, it is important to consider other plausible diagnoses (Figure 1).
Additionally, the manifestation of symptoms and signs depends on the rate of onset and the degree of elevation – those who develop severe hypercalcaemia in a short time frame are most at risk.
Key Points in the History:
- Establish the cancer type and history of progression, including treatment
- Cross-check medication history and stop any that induce rises in serum Ca2+ if possible
- Cross-check their use of any over the counter supplements
A group of blood tests, sometimes referred to as “the bone profile”, can be useful when managing a patient with hypercalcaemia:
- Serum Ca2+ – total + adjusted values
- Serum PO43-
- Alkaline phosphatase
- Albumin (to allow for correction)
- Total protein (if raised but albumin is normal, consider serum protein electrophoresis for the possibility of multiple myeloma)
NOTE – an ECG is also an important investigation to identify if there are any aberrations in the cardiac rhythm
Additionally, the following can be measured to delineate the cause of hypercalcaemia:
- PTH and Vitamin D
- Serum protein electrophoresis
Approach to Management
The treatment of severe hypercalcaemia involves rehydration therapy, calcium-lowering agents and long-term drug and lifestyle modifications.
NB – if mild or moderate hypercalcaemia with few signs and symptoms and a gradual onset, a conservative approach may be adopted.
Hypercalcaemia has acute and chronic impacts on the kidney. In the acute phase, high serum Ca2+ levels have two consequences which affect the glomerular filtration rate:
- Renal vasoconstriction – directly reduced GFR by increasing vascular resistance
- Inhibits Ca2+ and Na+ reabsorption within the tubule – the loss of Na+ (and H2O) in the urine results in volume contraction, which will further reduce GFR
Hence, an acute kidney injury is common for patients with hypercalcaemia and the first phase of treatment involves the administration of intravenous crystalloid therapy.
NB – long term hypercalcaemia can also induce concentrating defects within the nephron, resulting in nephrogenic diabetes insipidus.
Bisphosphonates are the primary calcium-lowering agents used in the setting of hypercalcaemia and they have an inhibitory action on osteoclasts through multiple mechanisms. Bisphosphonates have the additional benefit of analgesia – particularly in those with bony metastases.
Currently, the bisphosphonates of choice are pamidronate, zoledronate and ibandronate. Together with rehydration therapy, many patients will have their serum Ca2+ normalised within 3 days, though the resolution of symptoms may take longer.
Other calcium-lowering agents:
- Octreotide – a somatostatin analogue used to inhibit PTHrP secretion
- Denosumab – a monoclonal antibody targeting RANKL
- Substitute any medications which increase serum Ca2+ levels
- Stop vitamin and calcium supplements