Endocrine Abstracts

Introduction

Paraneoplastic hypercalcemia is extremely rare in the pediatric population, requiring urgent treatment. Pediatric malignancy-related hypercalcemia (PMRH) has been associated with rhabdomyosarcoma (RMS). Hypercalcemia with elevated parathyroid hormone (PTH), ectopic PTH secretion, is rarer (< 1% of cases). Reports of the use of Zoledronic Acid (ZA) as a second line bisphosphonate are limited. The monoclonal antibody, Denosumab, which inhibits RANKL-mediated osteoclast activity may be effective when bisphosphonates are not. The aim of presenting this case of PMRH secondary to ectopic PTH secretion was to highlight the benefits of ZA as a first choice bisphosphonate and Denosumab as an alternative therapy.

Case

The patient was diagnosed at 12.5 years with alveolar RMS. He had three subsequent relapses. Multiple bone metastases first appeared at 15.5 years but he remained normocalcemic until 17.5 years when serum calcium (Ca) was 14.9 mg/dl, ionized-Ca 2.36 mmol/l, phosphate 3.27 mg/dl, alkaline phosphatase 154 U/l, PTH 249 pg/ml, and 25-OHD 15 ng/ml; urinary Ca/Cr ratio 0.77. The patient was dehydrated and debilitated. Nephrocalcinosis and primary hyperparathyroidism were excluded by ultrasonography. Aggressive hydration and furosemide didn’t reduce hypercalcemia. ZA was given immediately (see Table 1). Although a good response was obtained following the first ZA cycle, there was a decrease in response to successive cycles. A single dose of Denosumab was given after the third ZA infusion, resulting in normocalcemia 72 hours later. There were no further hypercalcemic episodes while PTH remained elevated (755 pg/ml). Hypophosphatemia occurred, requiring treatment.

Discussion and conclusion

RMS is a non-parathyroid tumor but may cause hypercalcemia through ectopic PTH secretion. PTH mRNA has been identified in RMS cells, implying activation of the gene and direct secretion of PTH. There is in vitro evidence that ZA directly sensitizes RMS cells to γδ T-cell cytotoxicity. Thus, for treatment of RMS with hypercalcemia there may be a two-fold benefit in using ZA. PMRH was likely due to ectopic PTH production. We believe ZA should be the bisphosphonate of choice in hypercalcemia with RMS while Denosumab is a new option in ZA-refractory cases; both are safe and effective.