Hypercalcemia, or abnormally high calcium levels in the bloodstream, is a serious metabolic complication frequently affecting individuals with cancer. This condition is formally known as Hypercalcemia of Malignancy (HCM) and represents a common paraneoplastic syndrome, meaning it is a distant effect of the cancer not caused by local tumor growth. HCM occurs in up to 30% of all cancer patients, often indicating an advanced stage of the disease. Significant elevation in serum calcium can lead to dysfunction in multiple organ systems, and severe cases are considered a medical emergency requiring immediate intervention.
How the Body Regulates Calcium
The body maintains calcium balance, known as homeostasis, through a precise feedback loop involving three primary organs: the bone, the kidneys, and the small intestine. Bone acts as the main reservoir, storing over 99% of the body’s calcium, which can be released into the circulation when needed. The kidneys regulate calcium by determining how much is filtered out in the urine versus how much is reabsorbed back into the blood. The small intestine absorbs dietary calcium, a process significantly influenced by Vitamin D.
The parathyroid hormone (PTH), secreted by four small glands in the neck, is the central regulator of this system. When blood calcium levels fall, PTH is released to restore balance. PTH stimulates osteoclasts in the bone, which break down bone tissue to release stored calcium. Simultaneously, PTH signals the kidneys to increase calcium reabsorption and promotes the conversion of inactive Vitamin D into its active form, calcitriol. This active Vitamin D enhances calcium absorption from food in the small intestine, keeping serum calcium within a healthy range.
The Primary Driver: Humoral Hypercalcemia
The most frequent cause of elevated calcium in cancer patients is Humoral Hypercalcemia of Malignancy (HHM), a systemic condition accounting for approximately 80% of all cases. HHM occurs when the tumor secretes a circulating factor that affects calcium regulation throughout the body. The specific culprit is a protein called Parathyroid Hormone-related Protein (PTHrP).
Many solid tumors, particularly squamous cell carcinomas of the lung, head, and neck, along with some breast and kidney cancers, produce and release large amounts of PTHrP into the bloodstream. Structurally, PTHrP is remarkably similar to the actual parathyroid hormone, allowing it to engage in molecular mimicry. It binds to the same receptors on bone and kidney cells that PTH normally uses, effectively tricking the body into believing it needs more calcium.
The binding of PTHrP to these shared receptors drives two major systemic effects. First, it powerfully stimulates osteoclast activity in the bone, leading to widespread bone breakdown and a constant influx of calcium into the circulation. Second, it causes the kidneys to retain calcium more efficiently, reducing the amount excreted in the urine. This dual action overwhelms the body’s natural regulatory systems, resulting in high blood calcium levels even when the cancer has not spread to the bone.
Hypercalcemia from Direct Bone Destruction
A second major mechanism, known as Local Osteolytic Hypercalcemia (LOH), is responsible for about 20% of cancer-related hypercalcemia cases. Unlike the systemic effects of PTHrP, LOH requires the cancer to have physically metastasized and established colonies directly within the bone tissue. Multiple myeloma and metastatic breast cancer are the most common causes of LOH.
Once tumor cells are established in the bone marrow or bone matrix, they secrete a variety of local signaling molecules, collectively known as osteolytic cytokines. These factors include substances like Interleukin-6 (IL-6) and Tumor Necrosis Factor (TNF), which act as powerful local stimulants. The cytokines activate and recruit osteoclasts specifically in the area surrounding the tumor deposit.
The intensified activity of these osteoclasts causes a localized, aggressive destruction of bone tissue, dissolving the mineralized matrix and releasing calcium directly into the local circulation. This focused bone destruction is driven by the tumor’s immediate presence in the bone microenvironment, rather than a hormone circulating systemically from the primary tumor site.
Less Common Causes and Clinical Consequences
Beyond the two major mechanisms, approximately 1% of HCM cases are caused by the tumor’s ectopic production of calcitriol, the active form of Vitamin D. Certain hematological malignancies, most notably lymphomas, produce an enzyme that converts inactive Vitamin D into calcitriol outside of the kidneys. This excess calcitriol dramatically increases the absorption of calcium from the small intestine, leading to hypercalcemia.
Regardless of the underlying mechanism, the clinical consequences of unmanaged hypercalcemia can be widespread and severe, affecting nearly every organ system. Symptoms often begin non-specifically with fatigue, weakness, and increased thirst (polydipsia). High calcium levels impair the kidney’s ability to concentrate urine, leading to frequent urination (polyuria) and subsequent dehydration.
Gastrointestinal issues, such as nausea, vomiting, and severe constipation, are common patient complaints. Neurologically, patients may experience confusion, lethargy, or cognitive changes, potentially progressing to stupor or coma in extreme cases. Identifying the specific mechanism—whether hormonal mimicry or direct bone destruction—guides the urgent treatment strategy, which may involve drugs that block bone resorption or counter the effects of the tumor-secreted factor.