Hypocalcemic choreoathetosis and tetany after bisphosphonate treatment

On the basis of several randomized controlled trials, zoledronic acid, a highly potent and long-acting bisphosphonate, is emerging as the new standard of care for managing skeletal morbidity in patients with advanced cancers involving bone.1 Symptomatic hypocalcemia after treatment with bisphosphonates has been described before.2,3 To our knowledge, this is the first report on a patient with hypocalcemic choreoathetosis after bisphophonate therapy. An 85-year-old man received an infusion of 4 mg zoledronic acid because of prostate cancer with extensive bone metastases. The day after the infusion, he developed perioral paresthesia and numbness and tingling in his extremities. He complained of new-onset debilitating fatigue and diffuse pain and stiffness in both legs. He was unable to stand or walk without the help of two people, while prior to bisphosphonate treatment he had been able to walk approximately 1,000 meters before claudication due to lumbar spine stenosis limited further walking. On admission, he appeared fidgety and gave the impression of general restlessness. He had increased tone, decreased distal sensation, and diminished reflexes in both legs. Plantar responses were flexor. Muscle power was normal, and there were no signs of disturbance of vigilance or mental function. His speech was slightly slurred. From time to time, he had selflimited painful tetanic spasms in both legs. The most striking neurological disturbances were brief paroxysms of unilateral or bilateral choreoathetoid arm movements. These episodes lasted up to a minute and occasionally appeared precipitated by movements such as reaching out. His past medical history was unremarkable for movement disorders and medication interfering with extrapyramidal motor systems or with psychotropic effects. Lesions in the basal ganglia and spinal cord compression were ruled out by magnetic resonance imaging. Laboratory tests revealed extreme hypocalcemia (0.7 mmol/L; normal: 2.15–2.6 mmol/L), while all other electrolytes were in the normal range. Calcium concentration corrected for albumin was identical to the measured calcium level. Creatine phosphokinase (CK) was highly elevated (2858 U/L; normal: 24–171 U/L), indicating rhabdomyolysis, while the myocardial-specific isoenzyme of CK was in the normal range ( 10% of CK). Parathyroid hormone (PTH) was significantly elevated (195 pg/mL; normal: 15–65 pg/mL). Electrocardiography (ECG) showed normofrequent sinus rhythm (70 bpm) with marked QT interval prolongation (496 ms). After initiation of treatment with calcium and vitamin D, the spells of choreoathetosis and tetany in his legs resolved within a few days and ECG showed normalization of QT time. Electrophysiological studies were compatible with mild to moderate distal symmetric axonal and demyelinating polyneuropathy. The patient declined further evaluation of the polyneuropathy because of lack of symptoms and was discharged from hospital with mild residual hypocalcemia after complete resolution of the presenting neurological symptoms. Neurological complications of hypocalcemia seem to be the consequence of loss of inhibition, primary neuronal hyperexcitability, or changes in permeability of muscle membranes. Clinically evident hypocalcemia, regardless of its cause, generally presents in milder forms and is usually the result of a chronic disease state.4 In patients with prostate cancer, increased calcium utilization by extensive osteoblastic metastases is hypothesized to be the primary phenomenon inducing hypocalcemia and compensatory hyperparathyroidism. In these patients, bisphosphonates may further reduce serum calcium and increase PTH levels, which could limit therapeutic effectiveness of bisphosphonates unless calcium supplementation were given in doses sufficient to maintain PTH in the normal range.5 We suppose that in our patient, preexisting asymptomatic chronic hypocalcemia worsened and was unmasked after bisphosphonate therapy. Rhabdomyolysis may have further reduced the level of metabolically active calcium by elevation of phosphates (from CK), lactate, and other anions that chelate calcium.4 Our case report illustrates that zoledronic acid may trigger severe symptomatic hypocalcemia with neuromuscular complications and new-onset movement disorders. To minimize adverse events, assessment and correction of calcium homeostasis before initiating zoledronate therapy are recommended.3