Profound hypocalcaemia after zoledronic acid treatment

To the Editor: Zoledronic acid is a new bisphosphonate treatment for hypercalcaemia of malignancy, multiple myeloma and documented bone metastases from solid tumours, in conjunction with standard chemotherapy.1 Transient hypocalcaemia, a side effect of bisphosphonate therapy, can occur with zoledronic acid.2

We describe a patient with transient severe hypocalcaemia after zoledronic acid treatment.

An 88-year-old white woman with multiple myeloma presented with left hip pain. Imaging revealed multiple lytic lesions in the spine, pelvis and upper femurs. She was commenced on zoledronic acid 4 mg and a 5-day course of melphalan 10 mg/day and prednisolone 100 mg/day. At this stage, her serum calcium concentration was 2.38 mmol/L (normal, 2.15–2.55 mmol/L) and serum phosphate concentration was 0.8 mmol/L (normal, 0.8–1.5 mmol/L). She had renal impairment with reduced creatinine clearance of 35 mL/min.

Nine days later, she underwent surgical repair of a duodenal ulcer. Post-operatively, she was found to be hypocalcaemic, with serum calcium concentration of 1.34 mmol/L and ionised calcium concentration of 0.78 mmol/L (normal, 1.14–1.29 mmol/L). Serum phosphate concentration was 0.4 mmol/L and magnesium concentration was 0.87 mmol/L (normal, 0.70–0.90 mmol/L). Her serum 25-hydroxyvitamin D concentration was 14 nmol/L (normal > 50 nmol/L) and her parathyroid hormone level was 44 pmol/L (normal, 1.5–8.0 pmol/L). The patient displayed no symptoms of hypocalcaemia and had negative Chvostek and Trousseau signs. Her QTc interval was normal. Her hypocalcaemia was managed with oral calcium carbonate 4.5 g/day and calcitriol 0.5 g/day. Ten days later, her total serum calcium concentration rose to 2.31 mmol/L and her phosphate concentration was 0.9 mmol/L.

Bisphosphonates inhibit osteoclast-mediated bone resorption, thereby reducing serum calcium concentration. Compensatory secondary hyperparathyroidism prevents significant hypocalcaemia by enhancing renal calcium conservation, 1,25-hydroxyvitamin D production, and osteoclastic bone resorption.1,2 In our patient, the 1,25-hydroxyvitamin D concentration was not measured. However, in view of the low 25-hydroxyvitamin D and impaired renal function, this level may have been low, further exacerbating the hypocalcaemia.

Transiently low phosphate concentration in this patient may be due to fasting and co-administration of 5% dextrose, as our patient was fasted for 3 days peri-operatively and given a combination of intravenous 5% dextrose and normal saline.

Vitamin D insufficiency afflicts a large proportion of the elderly population,3 and its existence needs to be recognised before commencement of bisphosphonate therapy, so that adequate calcium and vitamin D supplementation can be given to reduce the occurrence of hypocalcaemia.