QuestionSBA
QuestionChoice
This may be considered as a second line to bisphosphonates. It works by increasing renal calcium excretion and reducing bone resorption by osteoclasts. It is useful in rapidly lowering calcium levels, but bisphosphonates would provide a more sustained effect
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Calcitonin
QuestionChoice
This is a parathyroid hormone analogue used as a second-line treatment for osteoporosis. It should not be used in this scenario as it will exacerbate hypercalcaemia
32236
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Furosemide
QuestionChoice
This is a parathyroid hormone analogue used as a second-line treatment for osteoporosis. It should not be used in this scenario as it will exacerbate hypercalcaemia
32234
b
Teriparatide
QuestionChoice
This patient has a likely new diagnosis of multiple myeloma, as evidenced by the anaemia, renal impairment, pathologic fractures and hypercalcaemia. Bisphosphonates are used in hypercalcaemia of malignancy and renal impairment should be considered when choosing a particular agent for initiation
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a
Bisphosphonates
QuestionChoice
This is a calcimimetic that works by increasing the sensitivity of the calcium-sensing receptor on the parathyroid gland, thereby lowering parathyroid hormone and calcium levels. It is typically used in medical therapy of primary hyperparathyroidism where surgery is not suitable. It would be a second-line agent in this scenario
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e
Cinacalcet
QuestionComment
previous question said myeloma didnt raise ALP as it doesnt increase osteoblast activity. is the raised ALP here from the fractures?
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# Summary

Hypercalcaemia refers to an abnormally high serum calcium, adjusted for serum albumin concentration. A calcium of over 2.6 mmol/L is generally considered high although laboratory reference ranges may vary slightly. The majority of cases are either due to primary hyperparathyroidism or malignancy, with other causes including medications, endocrine diseases such as hyperthyroidism and granulomatous diseases such as sarcoidosis. Mild cases are usually asymptomatic; symptoms can be remembered using the "stones, bones, groans and moans" mnemonic (referring to renal stones, bony pain, abdominal pain and psychiatric manifestations such as depression, anxiety and psychosis). Investigations include an ECG, bloods including a parathyroid hormone (PTH) level and a chest X-ray to look for evidence of malignancy or granulomatous disease. Conservative management may be appropriate for mild cases, with treatment of the underlying cause. Patients with moderate, severe or symptomatic hypercalcaemia are usually treated with intravenous fluids initially, followed by an intravenous bisphosphonate if required.

# Definition

The normal range for serum calcium is approximately 2.2-2.6 mmol/L. This is adjusted for serum albumin levels, which is important as approximately 40% of serum calcium is bound to albumin and so when albumin levels are low, serum calcium will be underestimated. 

99% of the body's calcium is stored in the skeleton and is crucial for the mineralisation of bone. It has many other roles in important functions such as muscle contraction, cardiac pacemaker activity, clotting, cell membrane stability and permeability.

Hypercalcaemia refers to an adjusted serum calcium of 2.6 mmol/L or higher - this should be repeated for confirmation. 

# Aetiology

- Primary hyperparathyroidism (most common cause)
    - Usually due to a solitary parathyroid adenoma 
    - Other causes include multiglandular parathyroid hyperplasia, an ectopic adenoma or a parathyroid cancer
    - 10% of cases are genetic (e.g. multiple endocrine neoplasia)
- Malignancy (second most common cause overall; commonest cause in hospitalised patients)
    - Commonest in breast and lung cancers, myeloma and leukaemia
    - May be paraneoplastic, for example due to tumour secretion of parathyroid hormone-related protein
    - May be due to osteolytic bone metastases causing release of skeletal calcium
- Granulomatous disease
    - Activated macrophages cause ectopic production of active vitamin D which increases calcium levels
    - Examples include sarcoidosis, tuberculosis, histoplasmosis and inflammatory bowel disease
- Tertiary hyperparathyroidism
    - Occurs in patients with longstanding secondary hyperparathyroidism due to chronic renal failure 
    - Parathyroid hypertrophy leads to excessive PTH secretion outside of normal homeostatic control, causing calcium levels to rise
    - Hypercalcaemia may be exacerbated if patients are also being treated with calcium or vitamin D supplement
- Medications 
    - Excessive calcium supplements
    - Milk-alkali syndrome (hypercalcaemia, metabolic alkalosis and acute kidney injury due to ingesting excessive antacids e.g. calcium carbonate)
    - Excessive vitamin D (including topical vitamin D analogues)
    - Lithium (via stimulation of PTH secretion and renal calcium reabsorption)
    - Thiazides (due to increased calcium reabsorption)
    - Vitamin A (due to bone resorption)
- Immobility 
    - Due to an imbalance in osteoclast and osteoblast activity
    - Usually only occurs if there is increased bone turnover e.g. Paget's disease
- Hyperthyroidism
    - Approximately 20% of patients have mild or moderate hypercalcaemia
    - Thought to be due to increased bone turnover
- Adrenal insufficiency
    - More rarely causes hypercalcaemia (approximately 8% of patients with Addison's disease)
    - Thought to be due to reduced renal excretion of calcium as well as dehydration
- Phaeochromocytoma
    - Tumours may produce ectopic PTH or PTH-related protein
- Familial hypocalciuric hypercalcaemia
- Benign autosomal dominant disorder
- The calcium-sensing receptor is mutated causing an insensitivity to calcium levels
- This leads to excessive PTH release, with resulting lifelong mild hypercalcaemia and hypophosphataemia
- Can be differentiated from primary hyperparathyroidism as urinary calcium is low rather than high

# Classification

- **Mild** hypercalcaemia - adjusted serum calcium **2.6-3.0** mmol/L
- **Moderate** hypercalcaemia - adjusted serum calcium **3.0-3.5** mmol/L
- **Severe** hypercalcaemia - adjusted serum calcium **> 3.5** mmol/L

# Signs and Symptoms

Mild hypercalcaemia is usually asymptomatic and is diagnosed as an incidental finding

A common mnemonic to remember symptoms of hypercalcaemia is "stones, bones, groans and moans":

- **Stones** - kidney stones causing renal colic
- **Bones** - bony pain and skeletal deformities; the underlying disease process (e.g. bone metastases or hyperparathyroidism) may lead to osteoporosis and increased fracture risk
- **Groans** - gastrointestinal symptoms of nausea, vomiting, constipation, abdominal pain, anorexia and weight loss
- **Moans** - neuropsychiatric symptoms of drowsiness, confusion, poor concentration and memory, depression, insomnia, anxiety, irritability and psychosis

Other symptoms include:

- Fatigue
- Lethargy
- Muscle weakness
- Thirst and polydipsia
- Polyuria and nocturia
- Flushing
- Pruritus

Signs include:

- Dehydration
- Hypertension
- Reduced consciousness
- Neuromuscular abnormalities - e.g. hypotonia, hyporeflexia, ataxia, decreased power
- Band keratopathy due to corneal calcium deposits (rare)

# Investigations

**Bedside:**

- **ECG** may show a shortened QTc (the most common abnormality); Osborn (or J) waves may be seen in severe hypercalcaemia and appear as a deflection at the end of the QRS complex
- **24 hour urinary calcium** will be high or normal in most cases of hypercalcaemia - if this is low familial hypocalciuric hypercalcaemia should be suspected
- **Urinary albumin:creatinine ratio** in patients with chronic renal impairment 
- **Sputum microscopy and culture for acid-fast bacilli** if tuberculosis is suspected

**Blood tests:**

- **Bone profile** to confirm hypercalcaemia - a single high reading should be repeated
- **PTH** should be suppressed; if it is normal or high hyperparathyroidism is the most likely cause (with familial hypocalciuric hypercalcaemia a differential)
- **Full blood count** may show anaemia related to malignancy or chronic disease (e.g. chronic kidney disease)
- **U&Es** may show renal impairment
- **ESR** and/or **CRP** to screen for inflammation, for example secondary to malignancy or tuberculosis
- **LFTs** for albumin; may be deranged if there are liver metastases from cancer; ALP may be raised due to increased bone turnover e.g. in hyperparathyroidism or bone metastases
- **Thyroid function tests** to rule out hyperthyroidism as
- **Vitamin D level** to rule out vitamin D toxicity; often low in primary hyperparathyroidism and should be replaced prior to parathyroidectomy to reduce the risk of hungry bones syndrome
- **Early morning cortisol** to rule out hypoadrenalism
- **Serum protein electrophoresis**, **serum free light chains** and a **blood film** to screen for myeloma
- Tumour markers e.g. **prostate-specific antigen (PSA)** in patients with suspected malignancy
- **Serum ACE** if sarcoidosis is suspected

**Imaging:**

- **Chest X-ray** as an initial screen for malignancy (either a lung primary or metastases) and to look for evidence of sarcoidosis or tuberculosis
- Further imaging may be indicated if malignancy is suspected, e.g. a **CT chest, abdomen and pelvis**
- **Dual-energy X-ray absorptiometry (DEXA)** assessment of bone mineral density to look for associated osteoporosis
- Renal imaging such as an **abdominal X-ray** or **ultrasound** to look for for renal stones or nephrocalcinosis

**Special tests:**

- **Genetic testing** may be offered to patients with suspected familial hypocalciuric hypercalcaemia and those with suspected inherited endocrinopathies (such as multiple endocrine neoplasia syndrome)

# Management 

**Conservative:**

- In some cases (e.g. familial hypocalciuric hypercalcaemia) no specific treatment is required
- Review medications and consider stopping these where possible (e.g. thiazide diuretics, calcium supplements)
- Advise patients to maintain an adequate fluid intake
- Patients should be referred to an appropriate specialist in most cases (e.g. endocrinology for suspected primary hyperparathyroidism, or via a two week wait pathway for suspected malignancy)
- Patients with severe hypercalcaemia require urgent medical treatment and so should be referred to hospital if seen in primary care

**Medical:**

- First line management is with IV fluids - this corrects dehydration, increases calcium excretion and is renoprotective
- An example regimen would be 4-6 litres of IV normal saline over the first 24 hours with regular fluid balance reviews to adjust as needed
- Following fluid resuscitation, intravenous bisphosphonates may be given to reduce osteoclast activity (e.g. zoledronate or pamidronate) - this takes 2-4 days to take full effect
- Patients may be continued on an oral bisphosphonate to help prevent recurrence
- Denosumab is an alternative for patients who cannot have a bisphosphonate (e.g. due to chronic kidney disease)
- Calcitonin is a second line option in hypercalcaemia of malignancy (although efficacy is limited)
- Steroids may be used and are most effective in hypercalcaemia secondary to sarcoidosis or vitamin D toxicity
- Vitamin D supplementation should be given where required with caution, in order to maintain levels in the normal range
- Cinacalcet is a second line option for patients with hyperparathyroidism (e.g. if unsuitable for surgery)

**Surgical:**

- Parathyroidectomy is the definitive management for primary hyperparathyroidism
- Indications to consider surgery include symptomatic hypercalcaemia, end-organ disease (e.g. osteoporosis, renal stones) or a calcium of 2.85 mmol/L or higher

# Complications

- Delirium
- Coma
- Arrhythmias e.g. ventricular fibrillation
- AVP-R (Nephrogenic diabetes insipidus) - due to degradation of aquaporin 2 channels, leading to polydipsia and polyuria
- Renal impairment (which may be prerenal due to dehydration as well as due to afferent arteriolar vasoconstriction) 
- Renal stones and nephrocalcinosis (calcium salt deposition in the renal parenchyma)
- Peptic ulcers (as hypercalcaemia triggers increased gastric acid production)
- Pancreatitis (rarely)

# NICE Guidelines

[NICE CKS - Hypercalcaemia](https://cks.nice.org.uk/topics/hypercalcaemia/)

# References

[BNF - Calcium imbalance](https://bnf.nice.org.uk/treatment-summaries/calcium-imbalance/)

[Patient UK - Hypercalcaemia](https://patient.info/doctor/hypercalcaemia)

[Life in the Fast Lane - Hypercalcaemia ECG Library](https://litfl.com/hypercalcaemia-ecg-library/)

[Royal United Hospitals Bath - Hypercalcaemia guideline](https://www.ruh.nhs.uk/pathology/documents/clinical_guidelines/PATH-016_Investigation_and_Management_of_HYPERCALCAEMIA.PDF)
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A 70 year old lady is admitted with a 1 month history of worsening lower back pain. She also reports feeling more fatigued and constipated recently.



Initial blood tests are as follows:



||||
|--------------|:-------:|---------------|
|Haemoglobin|102  g/L|(M) 130 - 170, (F) 115 - 155|
|White Cell Count|9.1x10<sup>9</sup>/L|3.0 - 10.0|
|Platelets|210x10<sup>9</sup>/L|150 - 400|
|Mean Cell Volume (MCV)|85 fL|80 - 96|
|Sodium|137 mmol/L|135 - 145|
|Potassium|4 mmol/L|3.5 - 5.3|
|Chloride|102 mmol/L|95 - 106|
|Urea|8 mmol/L|2.5 - 7.8|
|Creatinine|181 µmol/L|60 - 120|
|Calcium|3.1 mmol/L|2.2 - 2.6|
|eGFR|43 mL/min/1.73m<sup>2</sup>|> 60|
|Albumin|40 g/L|35 - 50|
|Alanine Aminotransferase (ALT)|21 IU/L|10 - 50|
|Aspartate Aminotransferase (AST)|32 IU/L|10 - 40|
|Alkaline Phosphatase (ALP)|266 IU/L|25 - 115|
|Bilirubin|7 µmol/L|< 17|
|Gamma Glutamyl Transferase (GGT)|20 U/L|9 - 40|





Thoracolumbar spine X-rays reveal multilevel compression fractures.



She is started on intravenous hydration.



Which of the following is the most appropriate treatment to initiate for her hypercalcaemia?
a