Refractory Hypocalcemia After Denosumab in a Patient with Metastatic Small Cell Lung Cancer

Denosumab is a monoclonal antibody against the receptor activator of nuclear factor kappa B ligand (RANKL), and it is considered one of the antiresorptive therapies used in metastatic bone lesions from solid tumors to prevent skeletal-related events (SREs). Although hypocalcemia is a recognized side effect of Denosumab, we are presenting a case of metastatic small cell lung cancer (mSCLC) with severe resistant hypocalcemia and hypophosphatemia after receiving a single dose of Denosumab for SREs. His calcium levels improved after adding Calcitriol. However, phosphates levels took far longer to correct even with parenteral replacement Very few cases have been reported with refractory hypocalcemia and hypophosphatemia in a patient with maintained kidney function.

Case Description:

A 62-year-old man who was recently diagnosed with advanced small cell lung cancer with metastases to liver, bone, and brain on chemotherapy with etoposide, carboplatin, and atezolizumab presented to the day-care unit to receive his scheduled dose of chemotherapy with a complaint of generalized fatigue and was found to have low calcium levels. Past medical history is significant for Chronic Obstructive Pulmonary Disease (COPD), rheumatoid arthritis (RA), hypertension, sleep apnea, and heavy smoking. He was treated with oral and IV calcium supplements and discharged home. Five days later, he presented with more generalized fatigue and weakness. Vital signs were within normal limits, and physical examination, including neurological assessment, was unremarkable.

Chemistries revealed a corrected calcium level of 1.61 mmol/L (2.2 -2.6 mmol/L), magnesium 0.63 mmol/L (0.7-1mmol/L), phosphorus 0.18 mmol/L (0.8-1.5 mmol/L), PTH 186 pg/ml, Normal Vitamin D level, and kidney function. ECG showed prolonged QT interval. The patient received Denosumab 120 mg subcutaneous for metastatic bone lesions three weeks prior to presentation. The patient was having bone pain and moderate hypercalcemia prior to treatment. Despite receiving around 7 g IV calcium gluconate and 300 mg Calcium lactate three times /day, levels remained low. Magnesium was corrected with an IV supplement. Phosphorous levels remained resistant to improvement despite oral or IV replacement. Calcitriol 0.5 mcg twice daily was added, and the oral supplement changed to calcium carbonate 1250 mg 3 times/day. Hypocalcemia normalized and reached 2.31 mmol/L.However, hypophosphatemia persisted.

Discussion:

Many cases with severe hypocalcemia after using Denosumab for SRE have been reported before, especially in patients with metastatic prostate cancer on hemodialysis. Few case reports showed refractory hypophosphatemia is a paraneoplastic manifestation of small cell lung cancer. This case represents a very uncommon presentation of concomitant resistant hypocalcemia and hypophosphatemia after Denosumab in patient with normal kidney function despite conventional electrolyte replacement. Calcitriol was used to treat hypocalcemia in our index patient, resulting in improvement of calcium levels. However, hypophosphatemia persisted.