Edited by: Claire Perks, University of Bristol, United Kingdom
Reviewed by: Arif Ansori, Airlangga University, Indonesia
*Correspondence: Azeez Farooki,
This article was submitted to Cancer Endocrinology, a section of the journal Frontiers in Endocrinology
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Hypercalcemia of malignancy (HCM) is a common clinical problem that is associated with considerable morbidity and negative effects on quality of life. Despite the availability of effective medical treatments for HCM, options are needed for cases that are refractory to conventional therapies. In this context, “refractory” refers to reasonable control of calcium in the setting of inpatient hospitalization (after receipt of standard of care therapies, such as continuous intravenous fluids, calcitonin, and intravenous bisphosphonates) with relapse into severe hypercalcemia within days or weeks of discharge from the hospital. Here we discuss drivers of hypercalcemia of malignancy and the physiologic mechanisms whereby they operate to increase serum calcium. Additionally, we discuss multiple available treatments targeted to a given contributory mechanism and also briefly discuss potential future treatments in need of further study.
Hypercalcemia of malignancy (HCM) is a common clinical problem that is associated with considerable morbidity and negative effects on quality of life. Despite the availability of effective medical treatments for HCM, options are needed for cases that are refractory to conventional therapies—this is most often seen in patients with solid tumors. In this context, “refractory” refers to reasonable control of calcium in the setting of inpatient hospitalization (after receipt of standard of care therapies, such as continuous intravenous fluids, calcitonin, and intravenous bisphosphonates) with relapse into severe hypercalcemia within days or weeks of discharge from the hospital. Inpatient readmissions may occur until, in a best-case situation, the use of antineoplastic therapy controls the tumor and the calcium level becomes manageable.
Multiple contributory mechanisms may lead to the development of treatment-refractory HCM. Benign primary hyperparathyroidism can coexist with HCM and should be identified as a possible contributor. It is generally excluded if the parathyroid hormone (PTH) value is <20 pg/mL (termed PTH-independent hypercalcemia). In addition to benign primary hyperparathyroidism, an elevated PTH value is present in parathyroid carcinoma and in rare cases of ectopic PTH secretion by tumors. The basic pathophysiologic mechanisms causing HCM include elevations in bone resorption, acceleration of gastrointestinal calcium absorption, and diminished renal calcium excretion.
Endocrine drivers of mechanisms that contribute to PTH-independent refractory HCM, with specific therapies for each mechanism.
| Mechanism | Driver | Therapy targeted to contributory mechanism | ||
|---|---|---|---|---|
| Endocrine | Other | |||
| Inappropriate calcitriol production | PTHrP production | Local osteolysis (advanced cancer in the bone) | ||
| Bone resorption | + | +++ | +++ | Intravenous bisphosphonates, denosumab |
| Gastrointestinal calcium absorption | +++ | * | – | Corticosteroids or other inhibitor of 1-alpha-hydroxylase; |
| Renal calcium reabsorption | – | +++ | – | Frequent intravenous fluids (normal saline with furosemide); cinacalcet |
| Hypophosphatemia (less CaPO4 = increased serum calcium) | – | ++ | – | Oral phosphorus |
Note that corticosteroids and phosphorus may be helpful regardless of the causative etiology. All mechanisms listed may be active in a given patient. For example, a patient with refractory hypercalcemia of malignancy may have all of the following: metastatic bone disease, high PTHrP level, hypophosphatemia, elevated calcitriol level, and relative hypocalciuria (relative to the degree of hypercalcemia, a calcium-retaining effect mediated by PTHrP). + relative contribution of a given mechanism; - lack of contribution; *potential indirect effect: only if high PTHrP stimulates calcitriol production.
Inhibition of osteoclastic activity or bone resorption is a validated strategy for treatment of HCM. At present, parenteral bisphosphonates and denosumab represent the most potent antiresorptives available. These drugs decrease bone turnover via inhibition of osteoclastic activity; since the process of bone turnover (sequential osteoclast activity followed by osteoblast activity) is tightly coupled, osteoblastic activity is also decreased. Together with standard of care therapies (intravenous fluids and subcutaneous calcitonin), the use of these agents often results in resolution of HCM; however, refractory cases are not uncommon in our experience. Furthermore, particularly when parenteral bisphosphonates and denosumab are used at an oncologic dosing frequency (monthly to every 3 months), rare but significant adverse effects, such as osteonecrosis of the jaw and atypical femur fracture (
What are the treatment options for cases of refractory HCM? To begin, a laboratory workup can help reveal the pathophysiologic mechanisms involved. Before the advent of intravenous bisphosphonates and denosumab, oral and intravenous phosphorus was used therapeutically to treat HCM (
Retrospective data from our group and other groups (Sheehan et al.
Accelerated renal tubular calcium reabsorption plays a significant role in cases of PTHrP-mediated HCM. In a well-hydrated hypercalcemic patient receiving normal saline, furosemide-induced calciuresis can be used to try to overcome the renal calcium retention induced by PTHrP; however, as the half-life of furosemide is 2 h, the beneficial effect of this approach is transient. Finally, repeated dosing of zoledronic acid weekly or denosumab once weekly can also be considered; one study showed a calcium-lowering benefit to weekly denosumab in subjects who had previously received intravenous pamidronate or zoledronic acid at the more standard monthly dosing (
Cases of refractory HCM that responded to cinacalcet in patients with solid tumors have been reported (
A PTH receptor antagonist is currently in preclinical development (
Refractory HCM is an understudied clinical problem with an unmet need for effective treatment options. Targeting the responsible pathophysiologic mechanisms involved is a clinically useful strategy. In some cases, this may involve the use of antiresorptive therapy, glucocorticoids, phosphorus, and possibly cinacalcet. New agents to add to our armamentarium for the treatment of refractory HCM are eagerly anticipated.
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
The author confirms being the sole contributor of this work and has approved it for publication.
National Institutes of Health grant P30CA008748 (to Memorial Sloan Kettering Cancer Center).
Special thanks to David Sewell for editorial assistance.
Dr. AF has consulted for Novartis and Amgen.
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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