Severe hypocalcaemia following denosumab in a patient with cancer with vitamin D deficiency

Abstract

Denosumab is a monoclonal antibody that has been widely used for the prevention of skeletal-related events in patients with cancer with solid tumours and bone metastases, and acts by reducing the release of calcium from bones into the bloodstream. Severe hypocalcaemia is a rare and dangerous side effect of denosumab. We present a case of a patient with metastatic prostate cancer who developed severe hypocalcaemia after receiving a single dose of denosumab. Further laboratory analysis showed that the patient had a low vitamin D level, which contributed to the development of hypocalcaemia. He required an inpatient admission for repeated doses of intravenous calcium.

Background

We report this case to emphasise the importance of ruling out pre-existing vitamin D deficiency prior to the initiation of denosumab. This may be an important measure in preventing hypocalcaemia related to denosumab and should be considered as a standard of care.

Case presentation

A 71-year-old man with a history of metastatic prostate cancer diagnosed in July 2017 when he presented with increased urinary frequency and widespread bone pain. His prostate serum antigen was found to be significantly elevated more than 4000 ng/mL. He underwent a prostate biopsy, which showed high-grade prostate adenocarcinoma with a Gleason score of 10. He had a CT scan of the chest, abdomen and pelvis, which showed diffuse lymphadenopathy, and bone scans showed diffuse skeletal metastases. The patient was initially started on bicalutamide in anticipation of antiandrogen therapy, but later opted for surgical castration instead of chemical castration. Given his initial presentation with high-volume disease, he was started on concurrent chemotherapy with docetaxel based on Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) trial data.¹ He also received radiation to symptomatic bony metastases. Repeat imaging after cycle 2 of docetaxel showed that the patient had a partial response to chemotherapy using Response evaluation criteria in solid tumors (RECIST criteria). Three months after initial diagnosis of prostate cancer, denosumab was started for prevention of skeletal events as a part of the management for metastatic prostate cancer to the bones. Twenty days after administration of first dose of denosumab and cycle 3 of docetaxel, the patient presented to hospital with febrile neutropaenia and fatigue. On evaluation, he was found to have severe hypocalcaemia. On admission, review of medications showed that the patient was taking amlodipine, vitamin D₂, gemfibrozil, furosemide and metoprolol succinate. On admission, vital signs were stable. Physical examination showed 1+ oedema in both lower extremities and negative Chvostek and Trousseau’s signs. ECG, however, revealed corrected QT (QTc) prolongation and laboratory workup on admission were significant for elevated creatinine of 1.9 mg/dL, a total serum calcium less than 5 mg/dL with an albumin of 2.4 g/dL (corrected calcium was less than 6.3 g/dL), ionised calcium of 2.8 mg/dL, urine calcium was less than 5.0 mg/dL, phosphorus level was 2.2 mg/dL, magnesium was 2.0 mg/dL, uric acid was 7.0 mg/dL and potassium was 4.7 mmol/L. He was also found to have an enterococcal bacteraemia with an unclear source, for which he was treated with ampicillin and responded very well. Laboratory studies done prior to starting denosumab showed serum calcium 8.3 mg/dL with an albumin of 2.6 mg/dL. During hospitalisation, his total serum vitamin D was noted to be low at 17 (normal range 31–100) ng/mL and initial parathyroid hormone (PTH) level was high at a level of 1213 pg/mL. His vitamin D levels were not checked prior to starting denosumab as this was not required per standard prescribing information. Figure 1 shows serum calcium levels during hospital stay. He was started on high doses of intravenous calcium supplementation after which he was switched to oral calcium as well as 50 000 units weekly of ergocalciferol, and calcitriol 25 μg daily. His total serum calcium rose up to 6.2 mg/dL, ionised calcium to 3.1 mg/dL and total vitamin D to 20 ng/mL.

Figure 1.

Depicts serum calcium measurements during prolonged hospital stay despite aggressive intravenous repletion of calcium.

Outcome and follow-up

The patient was discharged after 8 days of hospital stay on oral vitamin D and calcium supplementation with close monitoring of his laboratories as an outpatient. He has been getting monthly denosumab without recurrence of hypocalcaemia. His recent CT scan of chest, abdomen, pelvis and bones scan which showed stable disease with no new metastases.

Discussion

Denosumab is a fully human monoclonal antibody which inhibits osteoclast maturation, function and survival by binding to the cytokine receptor activator of nuclear factor-kappa ligand, reducing bone resorption.² In 2010, as a result of the Fracture Reduction Evaluation of Denosumab in Osteoporsis Every 6 Months (FREEDOM study), denosumab was approved for the treatment of postmenopausal women with osteoporosis at high risk of fracture, and has subsequently been approved to use for the prevention of skeletal-related events (SREs) in patients with multiple myeloma and in patients with bone metastases from solid tumours. In our patient, denosumab was administered for the diagnosis of metastatic prostate cancer to the bone to prevent SREs.³

SREs are seen as the complication of metastases of prostate cancer which can lead to fractures, severe pain, increased risk of death, increased healthcare costs and reduced quality of life.⁴ Based on the National Comprehensive Cancer Network (NCCN) guidelines, the use of denosumab or zoledronic acid is recommended to prevent SREs.⁵ However, in analyses of phase III trials, it was shown that denosumab was superior to zoledronic acid in preventing SREs.⁶ Moreover, in a meta-analysis from three randomised controlled trials in 4050 patients, it was found that denosumab was more effective than zoledronic acid in reducing the incidence of SRE in patients with bone metastases.⁷

In a systematic review, it was found that from 8990 patients with solid tumours, 5.2% developed hypocalcaemia.⁸ Another study found that the incidence of hypocalcaemia with denosumab was higher than zoledronic acid (12.4% vs 5.3%).⁹ Finally, it has also been shown that among patients who developed hypocalcaemia, the median time to serum calcium nadir was 21 days and the median time to correction of hypocalcaemia was 71 days.¹⁰

From a case series of 60 patients with metastatic castration-resistant prostate cancer at Memorial Sloan Kettering Cancer Center, 9 (15%) patients had severe hypocalcaemia due to denosumab requiring hospitalisation or intravenous calcium supplementation. Three of the nine patients had vitamin D deficiency, values less than 20 ng/mL, as per Endocrine Society vitamin D deficiency is defined as serum values less than 20 ng/mL. So, it was found that vitamin D deficiency appears to be a significant risk factor for developing denosumab-associated hypocalcaemia.¹¹ Retrospective trial data showed that vitamin D and/or calcium supplementation decreases the risk of denosumab associated hypocalcaemia (HR 0.60; 95% CI 0.45 to 0.81; p=0.0007).⁹

Other case reports in literature also highlight that low vitamin D levels are likely to predispose patients to develop hypocalcaemia.¹² Our patient was found to have elevated serum PTH level which indicates that the cause of hypocalcaemia could be from vitamin D deficiency, chronic kidney disease (CKD) or pseudohypoparathyroidism. However, our patient had hypophosphataemia, which is seen in secondary hyperparathyroidism due to vitamin D deficiency rather than in CKD, or pseudohypoparathyroidism in which the serum phosphorus level is usually high. Our patient also had low urinary calcium, which corroborated that the cause of hypocalcaemia was due to vitamin D deficiency. Before administering denosumab, our patient’s vitamin D levels were not evaluated. However, they were later found to be low, possibly contributing to the development of severe hypocalcaemia (<5 mg/dL). Although he was on standard calcium and vitamin D supplementation, with initiation of denosumab as part of the standard of care, he would have benefited from more aggressive treatment of vitamin D deficiency prior to therapy from denosumab.

We evaluated for alternate reasons such as renal dysfunction, which could have predisposed our patient to have severe hypocalcaemia. Renal dysfunction is reported in a literature as a risk factor for hypocalcaemia in a patient who received a single dose of denosumab. Hypocalcaemia was found in 24% of patients with glomerular filtration rate (GFR) <30 mL/min, versus 3% incidence in a group with GFR >30 mL/min.¹³ Another retrospective study performed in 14 patients with CKD stages IV–V who were treated with denosumab for osteoporosis, found that about 50% of patients developed hypocalcaemia while two of them developed severe complications of hypocalcaemia (seizure and prolong QTc).¹⁰ In our patient, we found his creatinine to be 1.9 mg/dL (same as baseline) and GFR=50 mL/min which, according to the aforementioned studies, would not have put him at a higher risk of hypocalcaemia.

Another risk factor for hypocalcaemia in patients with prostate cancer with bone metastases who received denosumab is high urine-N-terminal telopeptide (u-NTx) levels. Koguchi et al reported that patients who develop hypocalcaemia following treatment with denosumab had a baseline u-NTx of greater than 100 nmol bone collagen equivalents/mmol creatinine.¹⁴ In our patient, we did not check u-NTX level. However, it might be one of the markers that we can be used to predict hypocalcaemia in a patient before receiving denosumab.

We considered other causes of hypocalcaemia such as tumour lysis syndrome and felt it was less likely to be in this case as it did not meet Cairo-Bishop criteria. Hypomagnesaemia was also taken under consideration but was later ruled out due to normal serum magnesium levels in the patient. A patient with sepsis can be associated with hypocalcaemia, however, the cause will be impaired PTH secretion and end-organ resistance to the action of PTH that will present with hypoparathyroidism rather than hyperparathyroidism observed in our patient.

With regard to the treatment of hypocalcaemia, the Society of Endocrinology recommends intravenous calcium gluconate supplementation for patients with serum calcium less than 1.9 mmol/L (<7.5 mg/dL) and/or symptomatic, for example, perioral and digital paresthesia, positive Trousseau’s and Chvostek’s signs, tetany and carpopedal spasm, laryngospasm, prolonged QT interval and arrhythmia including seizures. Intravenous calcium gluconate can be repeated until the patient is asymptomatic after which the treatment can be switched to oral calcium and vitamin D supplements.¹⁵ In our patient, given that his serum calcium was less than 7.5 mg/dL and he had QTc prolongation, he met severe hypocalcaemia criteria and received intravenous calcium supplementation which was later on switched to oral calcium supplements. Vitamin D deficiency was treated with 50 000 IU vitamin D₂ (ergocalciferol) every week as per Endocrine Society guidelines.¹⁶

In conclusion, vitamin D deficiency is one of the risk factors that can precipitate severe hypocalcaemia in a patient who received denosumab. Even though there is sufficient evidence in case series and reports, regarding the association of hypocalcaemia related to concomitant vitamin D deficiency in a patient receiving denosumab, current guidelines still do not recommend checking vitamin D level prior to denosumab administration. Our case highlights the need to check for and correct vitamin D deficiency prior to initiation of therapy of denosumab and close monitoring of calcium levels after treatment especially around 2–3 weeks.

Learning points.

• Vitamin D deficiency is one of the risk factors that can precipitate severe hypocalcaemia in patients who received denosumab.

• It is paramount to check vitamin D 25-OH and serum calcium levels prior to denosumab administration and to correct before treatment start.

• Calcium levels should be monitored during and after treatment especially around 2–3 weeks.