Rebound hypercalcemia after denosumab cessation during follow-up after surgical treatment for parathyroid carcinoma: case report and literature review

Denosumab is a potent antiresorptive medication, commonly used in the treatment of osteoporosis, as well as in a variety of other diseases. Potential adverse rebound effects after its cessation include a loss in bone mineral density and an increased risk of osteoporotic fractures. Hypercalcemia is a less frequently reported rebound phenomenon after denosumab discontinuation, that may pose a diagnostic challenge to physicians as a rare non-parathyroid hormone (PTH) dependent cause of hypercalcemia. In our case, a 47-year-old male presented with rebound hypercalcemia after denosumab cessation during follow-up after surgical treatment for parathyroid carcinoma. This nonPTH-dependent hypercalcemia resolved after re-initiation of denosumab. We performed a systematic literature review on rebound hypercalcemia after denosumab cessation and identified 52 individual patient cases. Children appear to be more prone to developing rebound hypercalcemia, which could be attributed to their higher baseline bone turnover, underlying conditions, or denosumab dosage regimens. In most cases, patients initially presented with acute and often severe symptoms of hypercalcemia that occur from 1.75 to 9 months after denosumab cessation (4 to 9 months in adults). Most effective treatment approaches to sufficiently decrease serum calcium levels were bisphosphonates or re-administration of denosumab. A watch and wait strategy may be sufficient in asymptomatic cases, which are less common and probably underdiagnosed. Subsequent antiresorptive treatment after denosumab cessation, which is a common practice in osteoporosis treatment, may reduce the risk of rebound hypercalcemia. As denosumab is a frequently used drug in patients with advanced malignant diseases and rebound hypercalcemia with low PTH levels may raise the suspicion for skeletal metastases, awareness of this rebound effect may be for particular relevance in such settings.