Mechanisms of Hypercalcemia in Multiple Myeloma
Multiple myeloma causes hypercalcemia primarily through increased osteoclastic bone resorption driven by cytokines produced by myeloma cells and bone marrow stromal cells. 1, 2
Primary Pathophysiologic Mechanisms
- Myeloma cells and bone marrow stromal cells produce multiple cytokines that stimulate osteoclast activity, including interleukin-1, interleukin-6, tumor necrosis factor, and receptor activator of nuclear factor kappa B-ligand (RANKL) 1
- The increased osteoclast activity leads to excessive bone resorption, releasing calcium from the bone matrix into the bloodstream 2, 3
- RANKL appears to be the final common mediator of osteoclastic bone resorption, regardless of which upstream molecules initiate the process 3
- Macrophage inflammatory protein-1alpha has been identified as another key mediator of osteoclastic bone resorption in myeloma 3
Additional Contributing Factors
- Dickkopf 1 (DKK1), which is overexpressed in myeloma patients, acts as a potent stimulator of osteoclast formation and activity 3
- The myeloma bone marrow microenvironment shows increased numbers of osteoclast precursors (CFU-GM), contributing to enhanced bone resorption 4
- In some cases, myeloma cells may produce parathyroid hormone-related protein (PTHrP), which can independently cause hypercalcemia 5
- Decreased bone formation in areas adjacent to myeloma cells further contributes to the imbalance between bone resorption and formation 4
Clinical Manifestations
- Hypercalcemia is among the most serious complications of myeloma and typically occurs in advanced stages of the disease 6
- It can progress rapidly and lead to acute renal failure and coma, which may become life-threatening 6
- Symptoms depend on severity and may include polyurie, polydipsie, nausées, confusion, vomissements, and myalgies 7
- Hypercalcemia is one of the CRAB criteria (hypercalcemia, renal insufficiency, anemia, and bone lesions) used to diagnose symptomatic multiple myeloma requiring treatment 1
Diagnostic Considerations
- True hypercalcemia must be distinguished from pseudohypercalcemia, which can rarely occur in multiple myeloma due to binding of calcium to abnormal immunoglobulins 8
- In pseudohypercalcemia, the total calcium is elevated but ionized calcium remains normal 8
- Conventional radiographs reveal abnormalities consisting of lytic lesions, osteoporosis, or fractures in 79% of patients with multiple myeloma at diagnosis 1
Management Implications
- Bisphosphonates (zoledronic acid or pamidronate) are the most effective therapy for hypercalcemia in multiple myeloma 7, 6
- Aggressive hydration with normal saline is an essential first step in treatment 2, 7
- Diuretics (e.g., furosemide) should only be administered after correction of intravascular volume 7
- Denosumab may be considered in patients with hypercalcemia refractory to bisphosphonates or with renal insufficiency 7
Understanding the mechanisms of hypercalcemia in multiple myeloma is crucial for appropriate management of this potentially life-threatening complication and for developing targeted therapies to prevent and treat myeloma bone disease.