Hypercalcemia of Malignancy: A New Twist on an Old Problem

Hypercalcemia associated with malignancy is an old clinical problem, first described by Fuller Albright more than 50 years ago. It can cause significantmorbidity in patients with cancer and is associated with a poor prognosis in most patients. Thus, it is important to understand the pathophysiology to properly diagnosis and treat this important clinical syndrome. The accompanying article by Goldner presents a comprehensive review of this topic, which includes the latest addition to our therapeutic armamentarium to lower pathologic increases in serum calcium concentration: the receptor activator of nuclear factor k B–ligand antibody denosumab. Goldnermakes several important points in this review. First, the clinician must determine if the hypercalcemia is indeed a result of malignancy, rather than just associated with a nonmalignant cause of hypercalcemia such as primary hyperparathyroidism. After this has been established, treatment is directed against the cancer as well as thehypercalcemia. Tumor-produced systemic factors, such as parathyroid hormone–related peptide (PTHrP) or 1,25dihydroxyvitaminD, or locally active factors in bone, such as interleukin-6 or tumor necrosis factor-a, disrupt normal calcium homeostasis by excessive stimulation of osteoclastic bone resorption, in addition to lesser effects, to increase renal tubular reabsorption of calcium to result in hypercalcemia. As such, the mainstay of supportive care is to block pathologic osteoclast activity and maintain adequate hydration. For many years, this therapy consisted of bisphosphonates and fluid hydration, and for the most part was effective, particularly with the advent of the potent bisphosphonate zoledronic acid. As therapy evolved to include the most potent bisphosphonates, our understanding of the pathophysiology also evolved. The discovery thatmost tumor osteolytic factors, either humoral or local, stimulated bone resorption via receptor activator of nuclear factor k B–ligand led to more potent therapy to block osteoclastic bone resorption with the monoclonal antibody denosumab directed against this powerful stimulator of osteoclast formation and resorption. Indeed, recent reports indicate that denosumab is effective to reduce serum calcium concentration in the setting of bisphosphonate resistance and is more effective than zoledronic acid to prevent hypercalcemia associated with bone metastases. One downside to this new and more potent treatment is the increased risk of hypocalcemia. Thus, calcium should be closely monitored with the use of denosumab. Furthermore, because the studies describing denosumab use are small or retrospective analyses, further clinical studies using denosumab in the setting of hypercalcemia of malignancy are indicated. A future molecular target for the treatment of hypercalcemiaofmalignancy involvesPTHrPrelated antibodies. In an animal model, PTHrP antibodies corrected hypercalcemia and also suppressed the release of cytokines associated with malignancy. Taken together, insight into the pathogenesis of hypercalcemia ofmalignancy has resulted in new and better therapy for an old but difficult clinical problem.