Calcium is a mineral essential for building strong bones, proper nerve and muscle function (including the heart), and blood clotting. The body tightly controls circulating calcium levels through a complex interplay of hormones, primarily parathyroid hormone (PTH), calcitonin, and Vitamin D. An elevated calcium level in the blood is called hypercalcemia, which signals an underlying health issue requiring immediate medical attention. While the link between high calcium and cancer causes anxiety, many conditions can lead to hypercalcemia, necessitating a comprehensive medical evaluation to determine the precise cause.
Understanding Hypercalcemia
Hypercalcemia is defined as a higher-than-normal concentration of calcium in the blood serum, generally considered above 10.5 milligrams per deciliter (mg/dL). This condition is classified by severity, ranging from mild (10.5 to 11.9 mg/dL) to moderate (up to 13.9 mg/dL). In the early stages, high calcium levels may not cause noticeable symptoms and are often discovered incidentally during routine blood work.
When calcium levels rise, they affect multiple body systems, leading to various physical symptoms often grouped as “stones, bones, groans, and psychic overtones.”
- Stones: Refers to the formation of kidney stones and increased urination.
- Bones: Indicates pain, fragility, and bone loss.
- Groans: Includes digestive issues like nausea, constipation, and abdominal pain.
- Psychic overtones: Describes neurological effects such as confusion, depression, fatigue, or memory problems.
Severe hypercalcemia, typically above 14.0 mg/dL, is a medical emergency that can lead to life-threatening complications like irregular heart rhythms or coma.
The Most Common Non-Malignancy Causes
The majority of hypercalcemia cases in the general population are caused by primary hyperparathyroidism (PHPT), not cancer. PHPT is an endocrine disorder where one or more of the four small parathyroid glands, located near the thyroid, become overactive. This overactivity causes the glands to secrete excessive parathyroid hormone (PTH), even when blood calcium levels are already high.
The excess PTH acts on the bones, kidneys, and intestines to raise calcium levels further. PTH signals bones to release stored calcium, increases kidney reabsorption, and boosts Vitamin D production, which increases calcium absorption from food. In most PHPT cases, the cause is a single, non-cancerous growth (adenoma) on one gland. This condition often progresses slowly, resulting in long-term, mild elevations in calcium.
Other non-malignant causes include Vitamin D toxicity, where excessive supplement intake significantly increases calcium absorption from the digestive tract. Certain medications, such as thiazide diuretics prescribed for high blood pressure, can also contribute by reducing calcium excretion by the kidneys. Rarely, conditions like severe hyperthyroidism or prolonged immobilization cause high calcium levels by increasing bone tissue breakdown.
How Malignancy Causes High Calcium
Cancer is a significant cause of hypercalcemia, particularly in hospitalized patients, and is termed Hypercalcemia of Malignancy (HCM). Tumors raise blood calcium primarily through two mechanisms: humoral hypercalcemia of malignancy (HHM) and local osteolytic hypercalcemia. HHM is the most common cause, accounting for about 80% of cases, and involves the tumor releasing a hormone-like substance called Parathyroid Hormone-Related Peptide (PTHrP).
PTHrP is structurally similar to natural PTH, allowing it to bind to the same receptors on bone and kidney cells. This binding mimics PTH action, leading to increased calcium release from bone and reduced kidney excretion, thus elevating calcium levels. HHM is commonly associated with solid tumors, such as squamous cell cancers of the lung, head, and neck, kidney, and breast cancers. Unlike PHPT, PTHrP-driven hypercalcemia tends to be more severe and rapidly progressive.
The second mechanism is local osteolytic hypercalcemia, accounting for approximately 20% of cases. This occurs when cancer cells directly invade the bone, causing bone tissue destruction (osteolysis). Tumors that commonly metastasize to bone, such as breast, lung, and prostate cancers, cause this localized breakdown. Cancer cells and surrounding immune cells release chemical messengers (cytokines) that increase the activity of osteoclasts, the cells responsible for bone resorption. Multiple myeloma, a cancer of plasma cells, is a prime example causing hypercalcemia through this extensive bone destruction.
Differential Diagnosis and Medical Evaluation
When a blood test reveals elevated calcium, a medical evaluation is initiated to identify the underlying cause (differential diagnosis). Since primary hyperparathyroidism (PHPT) and malignancy account for the vast majority of cases, the initial investigation focuses on distinguishing between them. The most important laboratory test for this distinction is the measurement of the parathyroid hormone (PTH) level.
The PTH test provides insight into the body’s calcium-regulating system. In PHPT, the PTH level is either elevated or inappropriately normal despite the high calcium, indicating malfunctioning parathyroid glands. Conversely, in hypercalcemia of malignancy (HHM), healthy parathyroid glands recognize the high calcium and appropriately suppress PTH production. Therefore, a low or suppressed PTH level strongly suggests a non-parathyroid cause, most commonly malignancy.
Further testing may be necessary to confirm the diagnosis and rule out other causes. If malignancy is suspected due to suppressed PTH, additional blood tests can check for PTHrP or abnormal active Vitamin D levels. A 24-hour urine calcium test helps differentiate PHPT from rare, benign genetic conditions. Specific imaging studies, such as specialized parathyroid or bone scans, may also be used to visualize a tumor or assess the extent of bone involvement, helping pinpoint the source of the calcium elevation.