Hypercalcemia, or abnormally high calcium levels in the bloodstream, is a serious metabolic complication affecting individuals with cancer. Often called Malignancy-Associated Hypercalcemia (MAH), it is the most frequent life-threatening metabolic disorder seen in people with advanced disease. The body tightly regulates calcium for nerve signaling, muscle contraction, and bone health; elevated levels disrupt these normal physiological processes. Recognizing that cancer can upset this delicate balance is the first step in understanding the urgency of MAH.
Cancers Most Likely to Cause High Calcium
Malignancy-Associated Hypercalcemia is estimated to affect between 10% and 30% of all adult cancer patients at some point during their illness. The risk varies significantly depending on the cancer type, which are generally divided between solid tumors and cancers of the blood.
Among the solid tumors, squamous cell carcinomas, particularly those of the lung, head, and neck, are frequently implicated. Breast cancer and kidney cancer (renal cell carcinoma) also show a high association. In contrast, cancers like prostate and colorectal cancer rarely lead to this complication.
Hematologic malignancies (cancers of the blood) also pose a significant risk, with multiple myeloma having one of the highest rates. Other blood cancers, including certain types of non-Hodgkin lymphoma and leukemia, are known to contribute to MAH cases. Developing hypercalcemia often indicates a more advanced stage of the underlying cancer.
How Cancer Elevates Calcium Levels
The cancer-related increase in blood calcium falls into three main categories of action.
Humoral Hypercalcemia of Malignancy (HHM)
The most common mechanism, accounting for about 80% of cases, is Humoral Hypercalcemia of Malignancy (HHM). This is seen primarily in solid tumors that secrete a protein known as parathyroid hormone-related protein (PTHrP). PTHrP acts as a false alarm signal because its structure closely mimics the body’s natural parathyroid hormone. This protein travels through the bloodstream and signals the bones to increase calcium release and the kidneys to reabsorb calcium rather than excrete it. Constant production of this protein results in sustained and often severe elevation of calcium in the blood, even without cancer cells present in the bone itself.
Local Osteolytic Hypercalcemia
A second significant mechanism, accounting for about 20% of cases, is Local Osteolytic Hypercalcemia. This occurs when cancer has metastasized directly to the bone, common in multiple myeloma and metastatic breast cancer. The invading cancer cells stimulate specialized bone-destroying cells called osteoclasts. These osteoclasts are activated to break down the bone matrix, which releases large amounts of stored calcium directly into the local circulation. Cancer cells achieve this by releasing various factors, such as cytokines, which enhance osteoclast activity and lead to bone destruction. This mechanism is localized to the sites of bone metastasis, but the sheer volume of bone destruction can systemically raise blood calcium.
Extrarenal Production of Calcitriol
The third, and rarest, mechanism involves the Extrarenal Production of Calcitriol. This is seen most often in lymphomas, particularly Hodgkin and some non-Hodgkin types. Malignant cells produce an excess amount of the active form of Vitamin D, known as calcitriol. Calcitriol’s normal role is to increase the absorption of calcium from the digestive tract. Excessive production leads to hypercalcemia via increased intestinal absorption of calcium. This mechanism is distinctly uncommon, representing fewer than 1% of all MAH cases.
Symptoms and Initial Treatment of Hypercalcemia
Symptoms of high calcium vary widely, often starting mild and nonspecific, but becoming more severe as levels rise rapidly. Early signs often include generalized fatigue, loss of appetite, and nausea. As the condition progresses, individuals frequently experience excessive thirst and increased urination, as the kidneys attempt to flush out excess calcium.
More severe symptoms affect the nervous system, leading to confusion, difficulty concentrating, and muscle weakness. Untreated, very high calcium levels can lead to life-threatening complications, including kidney failure and abnormal heart rhythms. Because these symptoms can mimic other issues, a blood test is necessary for a definitive diagnosis.
Immediate management of acute hypercalcemia focuses on rapidly lowering calcium levels to prevent organ damage. The foundational step in initial treatment is aggressive intravenous (IV) fluid hydration, typically with saline solution. This fluid corrects dehydration and promotes the excretion of calcium by the kidneys. After hydration is initiated, medications are used to stop the bone from releasing more calcium. Bisphosphonates, such as zoledronic acid, are commonly administered to slow the activity of bone-destroying osteoclasts. For patients who do not respond adequately to bisphosphonates, or in severe cases, a targeted drug like denosumab may be used to block the signaling pathway that stimulates osteoclast activity.