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Hypercalcemia of Malignancy

Pathophysiology Diagnosis and Treatment

  • Therapy in Practice
  • Published:
American Journal of Cancer

Abstract

Hypercalcemia of malignancy (HCM) is the most common cause of elevated serum calcium in hospitalized patients and is found with varying frequency in patients with various types of cancer. Calcium homeostasis is finely regulated with day-to-day variations of less than 2%, and the development of HCM stems from various anomalies in homeostatic mechanisms. Hypercalcemia often produces a number of clinical symptoms, including alterations in central nervous system function, symptoms of dehydration and renal dysfunction. Whenever possible and appropriate, the goals of treatment of HCM should therefore be to return the patient to a euvolemic state, to normalize serum calcium and to treat the underlying cause. Almost invariably, however, HCM is a particularly adverse complication for patients with cancer and is almost always associated with a dismal prognosis. Older treatments like mithramycin and calcitonin have recently been replaced with newer management strategies, mostly involving bisphosphonates. These agents are potent inhibitors of osteoclasts which have been found to normalize serum calcium levels in a high proportion of patients with HCM. Emerging therapeutic approaches include monoclonal antibodies to parathyroid hormone related peptide (PTHrP), inhibition of RANK ligand through the use of a soluble form of its receptor osteoprotegerin, analogues of Vitamin D and selective inhibiton of the Ras-Raf-MAPK-ERK signalling pathway. In this article, we review the pathophysiology of tumour osteolysis leading to hypercalcemia of malignancy, and we discuss the physiological basis for the clinical symptoms of hypercalcemia. Past, current and future therapeutic approaches are also reviewed.

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Acknowledgements

Dr Hotte is a clinical scholar supported by a fellowship grant from the Canadian Institute of Health Research (CIHR), the Canadian Association of Medical Oncology (CAMO) and Eli Lilly Pharmaceuticals. Dr Major is an investigator for several clinical trials with bisphosphonates supported by Novartis and has served as an advisor to Novartis for a FDA meeting. P. Major and his collaborator, R. Cook have received a grant to pursue statistical studies on the methods of analysis of recurrent skeletal events.

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  1. Hamilton Regional Cancer Centre, 699 Concession Street, Hamilton, ONT, L8V 5C2, Canada

    Sebastien J. Hotte, Hal W. Hirte & Pierre P. Major

  2. Departments of Medicine and Oncology, McGill University, Montreal, Quebec, Canada

    Shafaat A. Rabbani

  3. Department of Surgical Sciences, Endocrine Unit, Uppsala University Hospital, Uppsala, Sweden

    Tobias Carling

  4. Departments of Pediatrics and Medicine, McGill University, Montreal, Quebec, Canada

    Geoffrey N. Hendy

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  1. Sebastien J. Hotte
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Hotte, S.J., Hirte, H.W., Rabbani, S.A. et al. Hypercalcemia of Malignancy. Am J Cancer 1, 179–187 (2002). https://doi.org/10.2165/00024669-200201030-00003

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