Hypercalcemia is a condition characterized by abnormally high levels of calcium circulating in the bloodstream. This metabolic disturbance is a common and serious complication of advanced cancer, formally referred to as Hypercalcemia of Malignancy (HCM). HCM indicates that the tumor has begun actively disrupting the body’s system for regulating calcium. This disruption occurs through the tumor’s ability to secrete substances that mimic or interfere with natural hormones. This article explains the biological pathways tumors employ to cause this imbalance.
How the Body Normally Controls Calcium Levels
The body maintains calcium levels within a very narrow range through a constant feedback loop involving several organs and hormones. The parathyroid glands, four small structures located near the thyroid in the neck, are the primary regulators of this system. These glands monitor calcium concentration in the blood continuously.
When blood calcium levels begin to drop, the parathyroid glands release Parathyroid Hormone (PTH). PTH acts on three main sites to restore balance: the bones, the kidneys, and the intestines. In the bones, PTH signals specialized cells to release stored calcium into the bloodstream.
In the kidneys, PTH promotes the reabsorption of calcium, preventing its loss in the urine. PTH also plays a role in activating Vitamin D, or calcitriol, which then travels to the small intestine. Activated Vitamin D is responsible for increasing the absorption of dietary calcium from the gut, completing the process of restoring calcium levels to normal.
The Primary Cause PTHrP Mimicry
The most frequent cause of elevated calcium in cancer patients is known as Humoral Hypercalcemia of Malignancy (HHM), which accounts for approximately 80% of all HCM cases. HHM is driven by the production of a substance called Parathyroid Hormone-Related Protein (PTHrP) by the tumor cells. This protein is secreted by many solid tumors, including squamous cell carcinomas of the lung, head, and neck, as well as some breast and renal cell cancers.
PTHrP is structurally similar to the body’s natural Parathyroid Hormone, especially in the segment responsible for binding to receptors. This similarity allows the tumor-secreted PTHrP to effectively hijack the body’s calcium-regulating machinery by binding to the same receptors that PTH normally uses on bone and kidney cells. PTHrP acts as a mimic, stimulating the same downstream effects as natural PTH, but in an unregulated manner.
When PTHrP binds to the receptors on bone cells, it dramatically increases the activity of osteoclasts, which are the cells responsible for breaking down bone tissue. This process, known as bone resorption, causes a rapid and widespread release of calcium from the skeleton into the bloodstream. Simultaneously, in the kidneys, the PTHrP molecule signals the tubules to increase their reabsorption of calcium, preventing its excretion in the urine.
The body’s natural response to this flood of calcium is to suppress the production of its own PTH. However, because the tumor is continuously secreting the PTHrP mimic, the calcium levels remain high despite the shutdown of the normal parathyroid response. This systemic overstimulation of calcium release and retention by the kidneys characterizes humoral hypercalcemia.
Other Ways Cancer Elevates Calcium Levels
While PTHrP is the most common cause, cancer can elevate calcium levels through two other distinct pathways. One mechanism is Local Osteolytic Hypercalcemia (LOH), seen primarily in cancers that have spread directly to the bone, such as multiple myeloma and certain breast cancers. Unlike the systemic effect of PTHrP, LOH involves the localized destruction of bone tissue at the site of the metastasis.
In this scenario, the cancer cells themselves, or the surrounding cells in the bone marrow, release local factors like cytokines and growth factors. These substances directly stimulate osteoclasts in the immediate vicinity of the tumor to aggressively break down the mineral matrix of the bone. This intense, localized bone destruction releases large amounts of calcium into the local blood supply, which then circulates throughout the body.
A third, less common mechanism involves the excessive production of active Vitamin D, or calcitriol, by certain malignancies, particularly lymphomas and some leukemias. Normally, the kidney carefully controls the final activation step of Vitamin D. However, some tumor cells gain the ability to perform this activation step outside of the kidney, resulting in uncontrolled calcitriol levels.
Excess calcitriol drastically increases the efficiency of calcium absorption from the food passing through the gastrointestinal tract. This over-absorption, combined with calcitriol’s mild effect on promoting bone resorption, contributes to the development of hypercalcemia. These two mechanisms, LOH and calcitriol production, often occur without the high levels of PTHrP that characterize HHM.
Recognizing Symptoms and Initial Treatment Approaches
The symptoms of hypercalcemia can range from subtle to life-threatening, affecting multiple body systems. Common initial complaints include fatigue, muscle weakness, and confusion or altered mental status. Patients frequently experience gastrointestinal issues like nausea, vomiting, and constipation.
High calcium levels impair the kidneys’ ability to concentrate urine, leading to excessive thirst and frequent urination. These renal effects can quickly cause dehydration, which in turn worsens the hypercalcemia, creating a dangerous cycle. Recognizing these non-specific symptoms is important for timely diagnosis.
Initial treatment focuses on rapidly and safely lowering the serum calcium concentration to prevent organ damage. The immediate treatment goal is aggressive fluid replacement using intravenous saline solutions to correct dehydration and promote the excretion of calcium through the kidneys.
Once the patient is rehydrated, specific medications are used to counteract the effects of the tumor-secreted factors. Bisphosphonates are commonly administered to block the activity of osteoclasts, slowing the rate of calcium release from the bone. Ultimately, the sustained solution for hypercalcemia of malignancy requires effective treatment of the underlying cancer, which removes the source of the calcium-elevating substances.