Hypercalcaemia to hypocalcaemia: tetany as a side effect of intravenous bisphosphonate treatment

Background

Hypercalcaemia of malignancy is an oncological emergency and should be treated urgently and bisphosphonates are a primary treatment strategy for people who develop it.1 We report the case of a woman in her 40s, who received intravenous bisphosphonate treatment for hypercalaemia. This resulted in a very low calcium level and associated carpopedal spasm of the hands and perioral anaesthesia.

The patient was admitted to hospital and treated initially with intravenous fluids and then given an infusion of zoledronic acid 4 mg. Several days after the infusion, she developed symptoms of tetany in the hands (manifesting as bilateral carpopedal spasms) as well as perioral paraesthesia. Her calcium had gone from high (3.53 mmol/L) to low (1.79 mmol/L). She was found to be vitamin D deficient during her admission.

The UK’s British National Formulary lists muscle spasms and electrolyte imbalances as a side effect of zoledronic acid, but neither the drug’s profile page, nor the bisphosphonate chapter list carpopedal spasm secondary to hypocalcaemia.2 Hypocalcaemia can be caused by bisphosphonate treatment, which can result in symptoms of cardiac arrhythmias and neurological symptoms such as convulsions, tetany and hypoaesthesia. Existing literature predominantly lists bisphosphonates causing hypocalcaemia when patients are receiving them for causes other than hypercalcaemia (ie, administered to initially normocalcaemic patients, while our patient had a hypercalcaemia at the outset).3 Tetany is a syndrome characterised by painful flexion of wrist and ankle joints (carpopedal spasm). It can also be associated with muscle cramps, twitching, seizures, laryngospasm, syncope or myocardial dysfunction. It occurs due to hyperexcitable nerves and muscles in the setting of decreased extracellular ionised calcium.4

On reviewing the literature, we found a case report describing a patient having received bisphosphonates who subsequently developed tetany of the legs and feet, rather than the hands as was the case in our patient.5 Low vitamin D levels can constitute an additional risk factor for developing hypocalcaemia, but our patient had a serum vitamin D level of 25 nmol/L, which is on the lower side of the normal reference range. Existing literature suggests that vitamin D deficiency can exacerbate bisphosphate-induced hypocalcaemia.6–9 It is recommended to assess calcium vitamin D and PTH status prior to commencing treatment with bisphosphonates.

Case presentation

A woman was admitted to the cancer hospital inpatient ward from the oncology clinic, due to newly deranged blood test results of hypercalcaemia (3.53 mmol/L; reference range 2.20–2.60) and hypokalaemia (2.1 mmol/L; reference range 3.5–5.0). She also had magnesium and phosphate deficiency.

The patient had been diagnosed with transitional cell carcinoma of the bladder (grade 3) invading through the posterior wall of the bladder. Her diagnosis came a year previously with initial lower urinary tract symptoms and severe flank pain. The CT urogram at this point revealed a right-sided hydronephrosis and hydroureter secondary to a primary bladder tumour. She underwent extensive treatment including a radical cystectomy and ileal conduit with a resulting urostomy and four cycles of adjuvant gemcitabine and cisplatin chemotherapy. Post-treatment scans revealed local recurrence of the right pelvic side wall. As such, she was offered local radiotherapy to the right pelvic wall and three cycles of atezolizumab immunotherapy thereafter, with the aim of control rather than cure. She had no other medical history and had never required treatment for hypercalcaemia prior to this.

Her symptoms on admission were unsteadiness, weakness, feeling muddled, fatigue, poor appetite and a general decline in function. On arrival, she received initial intravenous fluids with electrolyte replacements. Intravebous zoledronic acid was given on day 2 of her admission, due to persistent hypercalcaemia refractory to intravenous fluids.

On day 6 of her admission, she developed acute carpopedal spasms of both hands and wrists, with bilateral rigidity in both hands. On the day these symptoms developed, she was found to be hypocalcaemic (1.82 mmol/L). Her left hand was affected worse than her right hand. The rigidity was severe enough that all her fingernails (bar those of her thumb) were painfully indenting into the skin of her left palm. The muscle contraction itself was not painful, but she was unable to open her left hand and hence her functional ability (such as holding cups, etc) was severely diminished. In addition, this new clinical presentation was distressing to her. There was no redness of swelling to the hands or wrists, apart from the indentations made by her fingernails. She also reported new perioral paraesthesia.

Investigations

The patient had sequential blood tests during her 9 days of admission as summarised in table 1. She remained persistently hypokalaemic despite intravenous and oral supplementation. On day 6 of admission, the symptoms of tetany were found in both hands and a repeat set of bloods confirmed hypocalcaemia. Subsequently, a vitamin D level was added on to the bloods which came back showing a mild deficiency. An ECG showed ST depression in leads V2–V4, T wave inversion and u waves, although a normal qTC interval. These findings were consistent with her hypokalaemia.

Differential diagnosis

Differential diagnoses considered by the clinical team included focal epileptic seizures, although the presentation would have been atypical.7 Other electrolyte disturbances, including hypomagnesaemia, hypokalaemia and hypophosphataemia could have been causative or contributory causes for her symptoms, including the muscle spasm and contractures, however, her symptoms improved when calcium was replaced. Her other electrolytes were resistant to the replacement regimens instituted.10

Her low adjusted calcium in fact persisted until day 9 and the refractory nature of the deficiency, despite best efforts to replace it, may have been contributed to by other electrolyte deficiencies. Low magnesium at the outset, for instance, can lead to a significant challenge in correcting hypokalaemia, hypocalcaemia and hypophosphataemia.10

Treatment

On admission from oncology clinic, she received initial fluid resuscitation and electrolyte replacements as summarised in table 2. Subsequently her eGFR improved from day 2. Zoledronic acid 4 mg was given on day 2 due to persistent hypercalcaemia refractory to adequate fluid replacement.

A trial of baclofen 5 mg tablets orally was commenced with good effect on day 6 of her admission to help ease the carpopedal muscular spasms in the hands and wrists. Occupational therapists were also involved to provide splints for the hands for comfort.

Outcome and follow-up

The patients carpopedal spasm resolved 1 hour after receiving oral baclofen, and she was able to hold a glass of water (she had not been able to do this during the acute episode). Her perioral anaesthesia improved once calcium had been supplemented. Her hand symptoms had gone by day 7 of the admission, however, her other electrolytes (potassium, phosphate and magnesium) remained low despite supplementation.

Baclofen works as a GABA-B agonist in the central and peripheral nervous system. It reduces muscle spasticity through inhibition of synaptic transmission in motor neurons that innervate muscle spindles11 For this reason it is commonly used to treat muscle spasms and spasticity in conditions such as multiple sclerosis, cerebral palsy and spinal cord injury, typically at a starting dose of 5 mg orally three times a day. A trial of baclofen was commenced in this patient at a dose of 5 mg three times a day. The patient showed good response within an hour of administration, with a considerable reduction in the level of carpopedal spasticity caused by the hypocalcaemia.

Other members of the multidisciplinary team who contributed to an improvement in her symptoms were the occupational therapists, who were quick to suggest hand splints to reduce discomfort.

The patient was transferred to the inpatient hospice for symptom control as per the patient’s expressed wishes mainly for pain control (she had pain from her metastatic disease). She continued oral calcium supplementation on discharge. By her own request, she did not wish to receive further blood tests after transfer to the hospice.

We reported this side effect via the Medicines and Healthcare products Regulatory Agency yellow-card scheme.