Clinical review
Lesson of the week Severe hypocalcaemia after being given intravenous bisphosphonate Rajesh Peter, Vinita Mishra, William D Fraser
Bisphosphonates are increasingly used to treat metabolic bone disease and as prophylaxis against metastatic bone cancer.1 2 Zoledronic acid is a new intravenous bisphosphonate licensed to treat hypercalcaemia of malignancy, but it has been used off licence as prophylaxis for metastatic cancer, bone pain, treatment of osteoporosis, and Paget’s disease of the bone. Zoledronic acid is 100 to 1000 times more potent than disodium pamidronate or oral alendronic acid, risedronate sodium, sodium clodronate, or disodium etidronate. A randomised controlled trial found that zoledronic acid is more effective than disodium pamidronate in treating hypercalcaemia of malignancy.3 Zoledronic acid does not cause the gastrointestinal side effects associated with oral bisphosphonates, but increased potency carries a higher risk of hypocalcaemia. We have recent experience of patients becoming hypocalcaemic after doctors gave intravenous bisphosphonates.
Case reports Case 1 A 49 year old man with transitional cell carcinoma of the bladder received chemotherapy with cisplatin, methotrexate, and vinblastine after resection of a tumour. His prechemotherapy adjusted calcium was normal. Despite four cycles of chemotherapy every two weeks he had bone pain due to metastases. Doctors gave him 4 mg of zoledronic acid and intravenous diamorphine after diclofenac sodium and co-proxamol failed to relieve his symptoms. His adjusted calcium six days before being given zoledronic acid was low (table). Three days after being given intravenous zoledronic acid, he had tetanic spasms and paraesthesia. Trousseau’s sign was positive and an electrocardiogram showed a long QT interval—474 ms (RR < 440 ms). His adjusted calcium was low and decreased further despite doctors giving him 50 ml of 10% calcium gluconate intravenously over six hours. His parathyroid hormone was increased, and he had low serum vitamin D. Doctors gave him 80 ml of 10% calcium gluconate over the next 24 hours and started oral chewable ergocalciferol tablets twice a day and 250 ng calcidol once a day. After 10 days, his calcium returned within the reference range. Case 2 A 59 year old man with carcinoma of the lung was unwell for three weeks. He had nausea, vomiting, decreased appetite, and profuse diarrhoea. At an outpatients’ clinic, investigations found hypercalcaemia and low parathyroid hormone (table). Admitting doctors started him on 0.9% sodium chloride. Magnesium on admission was low. Doctors gave 4 mg of zoledronic acid, and his adjusted calcium decreased to BMJ VOLUME 328
7 FEBRUARY 2004
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within the reference range in five days. Two days later, he developed peri-oral paraesthesia and numbness and tingling in his extremities. Despite giving him calcium gluconate, his adjusted calcium and magnesium remained low. Doctors gave 40 mmol of magnesium sulphate over 48 hours in addition to calcium gluconate; his adjusted calcium increased into the reference range in seven days. Case 3 A 50 year old woman was admitted with an abdominal mass. Computed tomography showing widespread lymphadenopathy indicated a non-Hodgkin’s lymphoma. On admission, her adjusted calcium after chemotherapy was high, and her magnesium was within the reference range. Admitting doctors gave her 0.9% sodium chloride and frusemide for three days, but her calcium concentrations remained high until she received 60 mg of disodium pamidronate, cyclophosphamide, vincristine, and dexamethasone. Five days later she developed tetany and hypocalcaemia. Low vitamin D concentrations were detected. Doctors gave 10 ml of 10% calcium gluconate, started calcium infusions, and oral chewable ergocalciferol tablets twice a day. She received 40 ml of calcium gluconate over two days. After 15 days her calcium increased to within the reference range (table).
Severe hypocalcaemia after giving bisphosphonates may be caused by pathology interfering with parathyroid function Department of Clinical Chemistry, Royal Liverpool University Hospital, Liverpool L69 3GA Rajesh Peter senior house officer Vinita Mishra specialist registrar William D Fraser professor Correspondence to: W D Fraser
[email protected] BMJ 2004;328:335–6
Serum analyte concentrations in patents given bisphosphonates
Reference range
Adjusted calcium (mmol/l)
Magnesium (mmol/l)
Parathyroid hormone (pmol/l)
2.20-2.60
0.75-1.00
1.1-6.8
Vitamin D2 (ng/ml) 15
Case 1 Before starting bisphosphonate
2.36
6 days before starting (after chemotherapy)
2.09
3 days after
1.17
4 days after
1.11
14 days after
2.36
21.9 0.70
22.4 35.4
