Case Presentation: A 75 year old man with castration-resistant metastatic prostate cancer (with bone metastases) was evaluated for hypocalcemia as an incidental finding, when he was admitted for hemorrhagic shock secondary to a bleeding duodenal ulcer. He was asymptomatic despite serum calcium of 7.4 without tetany or EKG changes. He is on abiraterone for prostate cancer, being managed by outside oncologist, although he is unaware of medication history. IV and oral calcium gluconate supplementation was initiated, but Calcium continued to drop (lowest =5). Workup revealed appropriately elevated parathyroid hormone (391pg/mL), normal vitamin D3 (49.6), low vitamin D2 (10.6ng/mL) and slightly elevated alkaline phosphatase (155 units/L). SPEP was unrevealing for monoclonal gammopathy. Hewas started on a calcium gluconate infusion in addition to calcitriol daily and ergocalciferol biweekly due to recalcitrant hypocalcemia. Even on these therapies, patient’s calcium remained low and mostly unaffected by supplements. With such clinical information, one would expect a compensatory increase in Alkaline phosphatase as well as hypercalcemia from osseous lesions, but the absence of these features made this case very complex and challenging. For further investigation, his oncologist was contacted who reported his recent serum calcium was 8.9 , when he received a dose of 120 mg subcutaneous denosumab. This explained his severe hypocalcemia without a significant increase in bone turnover and unresponsiveness to supplements. Patient continues to be on vitaminD and calcium supplementation managed inpatient while we monitor his Calcium levels. His alkaline phosphatase is trending down (total iPTH =86, bone fraction 73%). He will be discharged on high dose calcium supplements once his calcium levels normalize.
Discussion: Denosumab (DMab), a human monoclonal antibody that binds RANKL, inhibits osteoclast activation and bone resorption; thereby increasing bone mineral density (BMD). DMab was recently approved (NCCN category 1) for use in prostate cancer with metastatic bone lesions after the success of the drug was documented in three large multi-center trials, with head to head comparison with zoledronate. Though effective, this medication carries an inherent risk for hypocalcemia by reducing bone turnover and “trapping” calcium in the bones. This risk is specially higher in patients with osteoblastic bone lesions, higher pre-treatment bone specific alkaline phosphatase, prior bisphosphonate use, GI malabsorptive diseases, pre-existing vitamin D deficiency and renal impairment. Severe hypocalcemia can develop usually after the first dose of denosumab, as far out as 2 weeks post therapy and can be very resistant to therapy. Our case highlights the importance of regular monitoring and the challenges faced in treating such patients.
Conclusions: Pretreatment screening for hypocalcemia is not enough in patients being treated with DMab. Profound and difficult-to-treat hypocalcemia can also develop within weeks (Median time of 16 days noted in a study) following its administration. Hence, regular monitoring should be a norm for early detection and treatment for this potentially devastating complication, which can lead to cardiac arrhythmias and death.