The Interpretation and Management of Hypercalcemia in Primary Care

This transcript has been edited for clarity.

In this podcast, I’m going to talk about the interpretation and management of hypercalcemia, or high calcium levels, in primary care. So, let’s start with some grassroots, simple calcium physiology.

Most of the calcium in our bodies is stored in bone. Calcium has a key role in skeletal mineralization. However, in addition to this role, calcium is involved in many pathways throughout the body, including enzyme pathways, muscle contraction, blood clotting, and maintaining a regular heart rhythm. Hence the wide range of symptoms and signs associated with abnormal calcium levels, which I’ll cover shortly.

Normal calcium range is around 2.15 to 2.60 mmol/L, but reference ranges and units will vary globally. We also often get a corrected calcium level reported to us in primary care. What’s the relevance of this? In the blood, around 40% of calcium is bound to proteins such as albumin. Abnormal albumin levels can make total calcium levels appear too high or low. Corrected calcium levels are a better indicator of the amount of calcium that is free in the blood for its physiologic functions. So, corrected calcium levels are recommended in particular for people with hypoalbuminemia, or low albumin levels.

Next, parathyroid hormone, or PTH, is the main regulator of calcium homeostasis and is secreted by the parathyroid glands in response to low calcium levels. PTH increases calcium reabsorption in the kidneys and stimulates conversion of vitamin D, which in turn promotes calcium uptake in the bowel. PTH also stimulates osteoclast activity to release calcium from bone. The overall effect of this is to increase blood calcium levels.

Finally, calcitonin is released by the thyroid C cells in response to increased calcium levels. Calcitonin stimulates osteoclasts to deposit calcium in the bone and inhibits the renal reabsorption of calcium, therefore increasing urinary calcium excretion. Calcitonin also reduces calcium uptake in the bowel. And the overall effect of this is to reduce blood calcium levels.

Calcitonin levels are not something we routinely check in primary care. Calcitonin levels are primarily checked to diagnose and monitor medullary thyroid cancer, particularly in those individuals with MEN, multiple endocrine neoplasia type 2, where screening is recommended.

Now let’s talk about hypercalcemia, or high calcium levels, which is a common finding in primary care. Calcium levels less than 3 mmol/L are usually asymptomatic and do not require urgent intervention by us in primary care. Levels above 3 mmol/L typically do cause symptoms but may be well tolerated if levels have risen slowly over time. However, we should consider hospital admission if calcium levels rise above 3.5 mmol/L or in the presence of severe symptoms due to the high risk for cardiac arrhythmias. Furthermore, at these levels of calcium, there is often an underlying malignancy driving the hypercalcemia.

So, what are the symptoms of hypercalcemia? I still remember the adage from medical school: bones, stones, moans, and abdominal groans, which summarizes the classic signs and symptoms of hypercalcemia.

First, bones: Hypercalcemia can cause vague muscle, bone, and joint pains or, rarely, fractures associated with underlying bone disorders. Next, stones: Hypercalcemia can cause kidney stones, polyuria, and polydipsia. Next, moans: Hypercalcemia can cause fatigue, low mood, muscle weakness, confusion, ataxia, and coma in severe cases. And finally, abdominal groans: Hypercalcemia can cause constipation, dyspepsia, nausea and vomiting, and pancreatitis.

What are the common causes of hypercalcemia? A key message for us all is that primary hyperparathyroidism and malignancy account for around 90% of all cases of hypercalcemia that we will see in primary care — a really useful message for us all. Primary hyperparathyroidism is where one or more of the parathyroid glands grows too large and releases too much PTH, which leads to elevated levels of calcium in the blood. Secondary hyperparathyroidism is where blood calcium or vitamin D levels are so low, often due to a dietary deficiency, that they cause the parathyroid glands to release excessive amounts of PTH to counteract the deficiency by inducing excessive release of calcium from the bone. Finally, tertiary hyperparathyroidism is where you have chronically reduced calcium and vitamin D deficiency that cause all four parathyroid glands to grow and produce PTH, regardless of whether the body needs the hormone, leading to elevated blood calcium levels.

Primary hyperparathyroidism is more common in women, with an estimated prevalence of 2.1% in postmenopausal women. It can also be part of familial syndromes as MEN, multiple endocrine neoplasia. Importantly, there’s often significant diagnostic delay between first presentation of hypercalcemia and subsequent diagnosis of primary hyperparathyroidism, something that is very important for us to be aware of in primary care.

Hypercalcemia of malignancy can be due to ectopic PTH production or lytic bone lesions. Common cancers causing hypercalcemia include multiple myeloma. Around 30% of people with multiple myeloma have high calcium levels at diagnosis. Breast cancer, lung cancer, kidney cancer, and prostate cancer can all also cause hypercalcemia.

Other causes of hypercalcemia include certain endocrine disorders, such as thyrotoxicosis, adrenal insufficiency and Addison's disease; granulomatous conditions such as sarcoid, tuberculosis, and inflammatory bowel disease; and certain drugs, including thiazide diuretics, lithium, calcium and vitamin D supplements — and don’t forget to ask about over-the-counter calcium and vitamin D supplements. Finally, chronic kidney disease and tertiary hyperparathyroidism and familial hypocalciuric hypercalcemia, which is a benign, autosomal dominant condition, can also cause hypercalcemia.

So, how do we investigate hypercalcemia? If there is evidence of persistent hypercalcemia above 2.6 mmol/L of any offending drugs or vitamin D preparations, then check PTH, urea and electrolytes, albumin, and vitamin D levels.

If PTH is elevated or normal, then the diagnosis is probably primary hyperparathyroidism. If PTH is low or undetectable, then exclude malignancy and the endocrine conditions that I've already mentioned. Investigations to consider include a chest x-ray, breast examination in women, and bloods for thyroid profile to exclude thyrotoxicosis, 9 AM cortisol to exclude adrenal insufficiency, a PSA test to exclude prostate cancer, and protein electrophoresis and Bence Jones proteins to exclude multiple myeloma, amongst other investigations.

I've produced a Medscape UK primary care hack or clinical aide-memoire on interpreting hypercalcemia and hypocalcemia in primary care for all healthcare professionals. I hope you find this resource helpful.

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Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.

Cite this: The Interpretation and Management of Hypercalcemia in Primary Care - Medscape - Apr 09, 2025.