Refractory Hypocalcemia after Denosumab Infusion for Treatment of Hypercalcemia of Malignancy

Logan L, Batiuk E and Mikhail N

Published on: 2026-02-24

Abstract

Denosumab is an anti-resorptive medication used for the treatment of osteoporosis, prevention of skeletal related events in patient with bone metastasis and for hypercalcemia of malignancy refractory to bisphosphonates. Refractory hypocalcemia following treatment with denosumab is a rare finding though has been recognized in cases involving chronic kidney disease, severe vitamin D deficiency, and osteoblastic metastases. We report a case of a 58-year-old woman with a history of Stage IV estrogen receptor positive, progesterone receptor positive, human epidermal growth factor receptor 2 negative (immunohistochemistry 2+) invasive lobular breast cancer with extensive bone metastases, who received denosumab for the treatment of malignancy associated hypercalcemia refractory to zoledronic acid. She presented with anxiety as well as perioral and bilateral distal lower extremity numbness and tingling and was found to have a serum calcium level of 6.1 mg/dL. Initial intervention involved oral calcitriol and calcium as well as continuous infusion of calcium gluconate to improve her serum calcium to mild hypocalcemia range. She had known diffuse osteoblastic lesions of the appendicular skeleton. Eventually, continuous calcium infusions were titrated down and altogether discontinued, with serum calcium levels corrected for albumin maintained in the low-normal range with high dose oral calcitriol and calcium carbonate. This patient’s clinical progression prompted concern for denosumab-induced refractory hypocalcemia in the setting of metastatic disease to the bone given refractory hypocalcemia more than six weeks after administration of denosumab. To the best of our knowledge, this is the first reported patient who developed prolonged and severe hypocalcemia lasting more than six weeks after a single dose of denosumab for the treatment of malignancy-induced hypercalcemia. More data is needed to identify potential risk factors for hypocalcemia, as well as closer monitoring of calcium levels and early calcium supplementation to reduce the risk of severe hypocalcemia in patients with osteoblastic metastasis being treated with denosumab.