Severe hypocalcemia and prolonged QT interval due to denosumab in an elderly woman with rheumatoid arthritis and chronic kidney disease

Abstract

Denosumab has been approved for the prevention of skeletal-related events of bone metastases (120 mg at every 4 weeks) and for the treatment of osteoporosis (60 mg at every 6 months). Post-denosumab hypocalcemia occurred in 5.2% of the cancer patients (1), but such an event was rarely reported in osteoporosis patients (2). Recently, severe hypocalcemia because of a lower dose of denosumab for osteoporosis has been reported in chronic kidney disease (CKD) patients (3, 4). We describe the first case of rheumatoid arthritis (RA) and CKD associated with severe hypocalcemia and prolonged QT interval after the administration of a lower dose of denosumab.A 73-year-old woman with a 10-year history of RA visited us for follow-up assessment. She denied having tetany or paresthesia but had noticed lightheadedness for a month. On conducting laboratory tests, her level of corrected calcium (cCa) was 6.7 mg/dL (Table 1). She had decreased estimated glomerular filtration rate (eGFR), consistent with moderate CKD through the equation from age and creatinine (5). Her electrocardiogram showed a corrected QT interval of 0.50 s (Figure 1). Seven months ago, the subcutaneous administration of 60-mg denosumab (Pralia, Daiichi Sankyo; Tokyo, Japan) was started for glucocorticoid-induced osteoporosis and for the multiple compression fracture of the spine (after obtaining informed consent from the patient), and the second dose was administered 4 weeks previously. She had undergone surgery for a thoracoabdominal aortic aneurysm 4 months previously. Since the surgery, her weight reduced by 6.5 kg. Her medication included prednisolone (4 mg daily), trichlormethiazide, furosemide, carvedilol, and olmesartan; subcutaneous abatacept was also administered. She had not taken any nutritional supplement during denosumab therapy. Denosumab was considered to be responsible for hypocalcemia. Following intravenous calcium gluconate administration, the level of cCa increased to 7.2 mg/dL. Two days after therapy with alfacalcidol and calcium, the level was restored to 8.9 mg/dL with the normalization of the QT interval; the level of intact PTH was elevated at 251 ng/mL (normal range, 10-65 ng/mL). Additional tests at the presentation showed a low level of 25-hydroxyvitamin D (6 ng/mL).In a randomized-controlled trial of denosumab for post-menopausal osteoporosis, hypocalcemia (cCa <8.0 mg/dL) was not reported for 3 years among the 3886 women administered with denosumab (2). Women having a level of 25-hydroxyvitamin D of <12 ng/mL were not included in the study, and all the subjects received calcium and vitamin D. Therefore, screening and supplementation of vitamin D deficiency may have played a role in the safety profile. Recently, the effect of 60-mg denosumab on serum calcium in CKD patients was investigated (3). Hypocalcemia (cCa <7.5 mg/dL) did not occur in 13 patients with an eGFR of 30-49 mL/min ) who were initially included and did not receive supplementation showed hypocalcemia, whereas seven patients with severe CKD receiving supplementation d...

Severe, Symptomatic Hypocalcemia due to Denosumab Administration: Treatment and Clinical Course

“…Stage 3B CKD is the likely explanation [18]. While CKD may predispose patients receiving denosumab to hypocalcemia [10, 19], it seems reasonable that it has a protective effect against hypophosphatemia, as is evidenced by our case as well as others [20, 21].…”

Comparative Safety and Effectiveness of Denosumab Versus Zoledronic Acid in Patients With Osteoporosis: A Cohort Study

“…(43) Severe hypocalcemia and subsequent QT prolongation has been also reported in patients treated with denosumab. (44,45) Nonetheless, this finding needs to be confirmed in other populations.…”

“…It is possible that hypocalcemia leads to development or exacerbation of heart failure . Severe hypocalcemia and subsequent QT prolongation has been also reported in patients treated with denosumab . Nonetheless, this finding needs to be confirmed in other populations.…”