Rebound hypercalcemia post denosumab therapy in an 8-year-old child: A case report

INTRODUCTION

Hypercalcemia, which occurs weeks to months after cessation of denosumab therapy, is a rare but important adverse effect seen predominantly in pediatric patients. The rebound hypercalcemia is often severe and needs prompt management. A high index of suspicion is needed for early identification and management of this potentially life-threatening adverse effect.

CASE REPORT

An 8-year-old male child presented with a history of persistent vomiting for 1 week. It was associated with intense nausea, intermittent abdominal pain, and headache. He had a history of constipation for 10 days before admission. There was no fever or abdominal distension. He had a significant history of an aneurysmal bone cyst of the second cervical vertebrae, which was medically managed with denosumab (70 mg/m²) 60 mg subcutaneously (4 weekly doses followed by monthly doses for 24 months). The cyst had shown remarkable improvement post therapy, and the last imaging showed residual lesions without any evidence of progression [Figure 1]. He has been off all medications for the past 3 months. On examination, he was conscious but tired and moderately dehydrated. He had a heart rate of 60/min with normal respiratory rate and blood pressure values. The systemic examination was unremarkable. He was started on intravenous fluids and other supportive care. The investigations showed normal complete blood counts, hypokalemia, and metabolic alkalosis. He had mildly deranged renal function tests with raised uric acid levels. The ultrasound of abdomen was suggestive of increased cortical echotexture of bilateral kidneys with poor corticomedullary differentiation. The magnetic resonance imaging of the brain and spine ruled out intracranial extension of the bone cyst lesion. The electrocardiogram, which was done in view of bradycardia, showed the presence of U waves, a moderately shortened QT interval, and a short and elevated ST segment, suggestive of metabolic abnormalities [Figure 2]. The serum total calcium level was 16.8 mg/dL with ionic calcium of 6.93 mg/dL in the presence of normal serum albumin levels, confirming severe hypercalcemia as the etiology for his clinical presentation. On further evaluation, the serum phosphorus level and serum magnesium were 2 mg/dL and 2.4 mg/dL, respectively. Vitamin D level was 14.4 ng/mL, and intact parathyroid hormone (PTH) level was 6.2 pg/mL, confirming a parathyroid hormone-independent cause of hypercalcemia.

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Figure 1:

Aneurysmal bone cyst pre and post denosumab therapy.

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Figure 2:

Electrocardiogram showing bradycardia, U waves, moderately short QT interval with short and elevated ST segment (black arrows).

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He was treated with isotonic saline rehydration followed by 2 doses of injection calcitonin (4 U/kg) subcutaneously and intravenous zoledronic acid (0.025 mg/kg) infusion. His calcium levels showed progressive reduction followed by spontaneous resolution of the deranged renal function tests and electrolyte abnormalities [Figure 3]. He continues to remain asymptomatic at 1-year follow-up.

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Figure 3:

Trends in calcium levels.

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DISCUSSION

Aneurysmal bone cysts (ABCs) are rare, benign, locally aggressive tumors that arise predominantly in long bones and spine, accounting for 1–2 % of total primitive bone tumors.^[1,2] Although surgery is the gold standard treatment option, it may not be feasible in pelvic and spine ABCs; thereby necessitating a need for alternative treatment strategies.^[1] Overexpression of the receptor activator of nuclear factor kappa-B ligand (RANKL), resulting in osteoclastogenesis and bone resorption, is the proposed pathogenic mechanism in ABCs.^[1] Denosumab is a human monoclonal antibody that binds to RANKL, thereby interfering with the RANKL/receptor activator of nuclear factor kappa-B interaction, which is responsible for differentiation and activity of osteoclasts.^[3] Hence, denosumab has been used as a potential therapy for bone disorders that are mediated through the RANKL pathway.^[2] Due to the histological similarities and the encouraging results of denosumab use in giant cell tumors, it has often been used as an off-label therapy in the management of ABCs, especially in cases of inoperable lesions.^[1,2]

Denosumab has a short half-life, resulting in rapid reversal of therapeutic effects after drug discontinuation.^[2] This is unlike bisphosphonates, which tend to bind to bone matrix, resulting in a sustained therapeutic action.^[2,3] Potential complications post denosumab discontinuation include rebound hypercalcemia, more frequently reported in pediatric patients, and rapid bone loss and vertebral compression fractures, which have been reported only in adults.^[2-4]

It is hypothesized that post denosumab discontinuation, the recovery of osteoclast activity results in a rapid resorption of bone, which triggers the release of calcium from the calcified tissue into the circulation, which in turn can lead to severe hypercalcemia.^[3] The exact mechanism of rebound bone turnover is not known, but it is probably the result of upregulation of osteoclast-promoting factors and/or changes in RANKL and osteoprotegerin production.^[2] Following denosumab treatment, higher proportions of osteoclast precursors have been detected in peripheral blood mononuclear cells.^[5]

The higher baseline bone turnover in children may be responsible for the higher risk of rebound osteoclastic activity.^[6] The diagnosis and other variables such as the age, growth rate, and activity of bone metabolism may also play an additional role.^[7]

In a retrospective study of nine pediatric patients who received denosumab for the treatment of ABCs, 2 out of the 9 patients (22%) developed severe rebound hypercalcemia at 5 months of drug withdrawal.^[8]

Maximen et al. reviewed 43 cases (mean age: 15.9 ± 8.1 years) of ABCs treated with denosumab reported in the literature.^[1] The study found that six patients (mean age of 9 ± 3.2 years) presented with hypercalcemia within a mean time interval of 5.3 ± 0.52 months after cessation of denosumab.^[1] Five out of these 6 patients had severe hypercalcemia needing intensive care therapy.^[1]

In a systematic review of 49 cases of denosumab-induced rebound hypercalcemia, 40 cases (82%) were children (<18 years of age).^[9] Younger patients were found to have a higher risk of developing severe hypercalcemia (median, 15.3 mg/dL vs. 12.4 mg/dL). They developed hypercalcemia following a shorter duration of denosumab therapy (median, 12 months vs. 16 months; P < 0.0001). The duration from discontinuation of denosumab to the onset of hypercalcemia was also shorter in younger patients (median, 4 months vs. 5.75 months; P = 0.017).^[9]

Ferriero et al. reported a case series of four children with Noonan syndrome and multiple giant cell lesions of the jaw treated with denosumab. All four of them developed hypercalcemia at 67–80 days of drug withdrawal and were treated with bisphosphonates.^[10]

In a case series describing four pediatric cases of osteogenesis imperfecta type VI treated with denosumab, hypercalciuria was noted in all the cases during the course of treatment.^[7] One child developed nephrocalcinosis.^[7] Two children developed rebound hypercalcemia between 7 and 12 weeks of denosumab discontinuation.^[7]

Rebound hypercalcemia post denosumab therapy is often severe and can present with symptoms such as fatigue, nausea, vomiting, constipation, abdominal pain, weight loss, polyuria, dehydration, renal failure, and sinus bradycardia.^[1,6,11] The Drug Safety Update published in May 2022 described a few cases of serious and life-threatening hypercalcemia requiring hospitalization and complicated by acute renal injury in pediatric patients who received denosumab for osteogenesis imperfecta in clinical trials.^[12] In these cases, hypercalcemia occurred during the treatment period or in the weeks to months following the last dose.^[12]

There are no recommended guidelines or treatment protocols for managing rebound hypercalcemia. Intravenous rehydration, diuretics, corticosteroids, bisphosphonates, calcitonin and/or repeat dosing of denosumab have been used in various case reports in the literature. Bisphosphonates (single dose or repeated) have been used in most of these reported cases with successful and sustained normalization of calcium levels.^[5,6,11]

Few case reports have dealt with the pre-emptive measures that can be undertaken to prevent rebound hypercalcemia post cessation of denosumab therapy. Precautions like gradually tapering the frequency of drug administration and/or dosage can be considered.^[3,6] Additional strategies directed toward the inhibition of osteoclastogenesis, thereby slowing down bone resorption, may be attempted.^[6] Some reports indicate that bisphosphonate treatment given at the time of discontinuation of denosumab may moderately reduce this rebound effect.^[2,6] Bisphosphonates get incorporated into the bone matrix and interrupt the osteoclasts’ activity when denosumab is stopped.^[6]

A pediatric patient with ABC who developed two episodes of hypercalcemia after withdrawal of denosumab was prophylactically treated with zoledronic acid when denosumab interruption was planned the 3^rd time. The child remained asymptomatic after receiving 4 doses of 6-monthly zoledronic acid.^[6] Oral alendronate, started about 6 weeks after the last denosumab dose and continued for 1 month, was successfully used to prevent rebound hypercalcemia in a pediatric patient.^[10]

At present, there are no guidelines regarding the frequency of laboratory monitoring of calcium levels during or post cessation of denosumab therapy. Hence, monitoring calcium levels at the end of treatment and possibly for a few months post cessation of therapy should be mandatory.^[11] Educating the children and their families about the clinical features of hypercalcemia will definitely help in early identification of the condition and reduce morbidity.

Cytofluorimetric analysis of peripheral blood monocytes to evaluate osteoclast precursors, particularly the cluster of differentiation (CD)16−/CD14+CD11b+ cells, has been proposed as a monitoring tool during the discontinuation phase.^[3] Further studies in this regard are warranted.

CONCLUSION

Rebound hypercalcemia is a serious side effect of denosumab therapy, predominantly seen in pediatric patients. Severe hypercalcemia typically develops around 3–5 months after the drug discontinuation. A high index of suspicion is needed for early identification and management of this potentially life-threatening adverse effect. Long-acting bisphosphonates, such as zoledronic acid, are highly efficacious in the treatment of rebound hypercalcemia post cessation of denosumab.