Most people think of calcium only in terms of bones and teeth, but calcium also plays a critical role in nerve signaling, muscle contraction, hormone release, and heart rhythm. Because of this, the body keeps blood calcium levels tightly regulated. When calcium levels rise too high it can affect nearly every organ system. Hypercalcemia is typically defined as a blood calcium level greater than 10.5 mg/dL (2.6 mmol/L).
The two most common causes of hypercalcemia are primary hyperparathyroidism and malignancy. In primary hyperparathyroidism, the parathyroid glands produce excess parathyroid hormone (PTH), which raises calcium levels by increasing calcium release from bone, enhancing kidney calcium reabsorption, and activating vitamin D to promote intestinal absorption. Malignancy related hypercalcemia tends to rise more rapidly and severely, and certain cancers produce PTH related peptide or cause bone destruction through lytic lesions, while others particularly lymphomas can increase activation of vitamin D.
Because calcium influences nerve and muscle function, hypercalcemia often produces neurological symptoms such as fatigue, confusion, slowed thinking, depression, and muscle weakness. In severe cases, coma can occur. This happens because elevated calcium stabilizes neuronal sodium channels, raising the threshold needed for nerves to fire, which leads to lethargy and reduced excitability, the opposite of twitching seen in low calcium levels. The cardiovascular system is also affected, with hypercalcemia shortening the QT interval on ECG and potentially causing arrhythmias and elevated blood pressure due to increased vascular smooth muscle contraction.
The kidneys are especially vulnerable to high calcium levels, and this is where many noticeable effects occur. Hypercalcemia can cause dehydration, increased urination, kidney stones, and reduced kidney filtration (GFR). This happens through several mechanisms. High calcium activates calcium-sensing receptors (CaSR) on the afferent arteriole, causing it to constrict and reduce blood flow into the glomerulus, which lowers GFR. Calcium also inhibits the Na-K-2Cl transporter in the thick ascending limb of the nephron (similar to how loop diuretics work) leading to sodium and water loss and worsening dehydration. Additionally, CaSR activation reduces the kidney’s response to antidiuretic hormone, impairing water reabsorption and producing a nephrogenic diabetes-insipidus–like picture.
Hypercalcemia also affects the skeletal system. In primary hyperparathyroidism, bone resorption increases over time, which can contribute to osteoporosis and bone discomfort. In malignancy related hypercalcemia, bone breakdown can occur far more rapidly. The gastrointestinal system may also be involved, leading to nausea, reduced appetite, constipation, abdominal discomfort, and in rare cases pancreatitis due to calcium activation of pancreatic enzymes. The classic teaching summary for hypercalcemia symptoms is “stones, bones, groans, thrones, and psychiatric overtones,” referring to kidney stones, bone pain, abdominal discomfort, increased urination, and mood or cognitive changes.
Treatment depends on both severity and underlying cause. The first line therapy for moderate to severe hypercalcemia is intravenous normal saline, which restores circulating volume, increases kidney perfusion, and enhances calcium excretion. Calcitonin can provide rapid but short term reduction in calcium, while bisphosphonates are especially useful in malignancy related cases because they inhibit bone resorption. Additional steps include stopping contributing medications such as thiazide diuretics or excessive calcium and vitamin D supplements. Underlying diseases must ultimately be treated such as parathyroid surgery for primary hyperparathyroidism or oncologic therapy in cancer related hypercalcemia.
Hypercalcemia becomes a medical emergency when calcium levels exceed 14 mg/dL (3.5 mmol/L) or when symptoms include severe dehydration, confusion, vomiting, or heart rhythm abnormalities. Recognizing the condition early is important because hypercalcemia disrupts kidney filtration, heart conduction, nerve signaling, hydration balance, gastrointestinal function, and bone metabolism. Understanding the physiology behind these symptoms makes hypercalcemia easier to identify, evaluate, and manage effectively.