Article, Endocrinology

Life-threatening hypocalcemia associated with denosumab in a patient with moderate renal insufficiency

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American Journal of Emergency Medicine

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Life-threatening hypocalcemia associated with denosumab in a patient with moderate renal insufficiency?,??,?

Abstract

Denosumab, a human monoclonal antibody to the receptor activator of nuclear factor-?B ligand, is a novel therapy to osteoporotic fracture and skeletal-related events in patients with Bone metastases. Hypocalcemia is its known adverse effect, although it is generally mild and transient and usually occurs in patients with severe chronic kidney disease or end-stage renal disease. We reported a case 61-year-old woman who received a single dose of denosumab and developed severe symptomatic hypocalcemia associated with prolong QTc interval requiring hospitalization for intravenous calcium.

Denosumab is a novel class of medicine that is approved for treatment of osteoporosis and prevention skeletal-related events in patients with bone metastases. Hypocalcemia was found in 5.5% to 13% of patient receiving this drug, although the decreases in serum calcium were generally mild, transient, and asymptomatic. Severe hypocalcemia, although uncommon, was observed in patients with chronic kidney disease.

A 61-year-old white woman presented to our institution with involuntary shaking of both lower and upper extremities resulting in a fall after she had watery diarrhea for 3 days. She had history of poorly controlled diabetes, which resulted in diabetic nephropathy with chronic kidney disease (CKD) stage 3. She was diagnosed with stage IV infiltrating ductal carcinoma of left breast 1.5 year earlier. She received neoadjuvant chemotherapy and underwent modified radical mastectomy. Unfortunately, 2 months before admission, she developed back pain and was found to have bone metastases. She was treated with radiation therapy as well as monthly denosumab. She received her first dose (and the only dose) of 120 mg of denosumab 1 month before the presentation. Her laboratory investigations before administration of denosumab revealed serum urea nitrogen of 28 mg/dL, creatinine of 1.6 mg/dL (estimated glomerular filtration rate using Chronic Kidney Disease Epidemiol- ogy Collaboration formula of 34.4 mL/min per 1.73 m2), ionized calcium of 4.9 mg/dL, phosphorus of 4.6 mg/dL, and parathyroid hormone (PTH) of 520 pg/mL. Her current medication included amlodipine, aspirin, levothyroxine, metoprolol, calcium carbonate, calcitriol, anastrozole, oxycodone, glipizide, and atorvastatin.

? Funding: None.

?? Conflict of interest statement for all authors: We do not have any financial or

nonfinancial potential conflicts of interest.

? Authors’ contributions: All authors had access to the data and a role in writing the

manuscript. This manuscript is original research that has not been published and is not under consideration elsewhere.

Physical examination in the emergency department was remark- able for carpopedal spasm and perioral paresthesias. Blood test revealed hypocalcemia with ionized calcium of 2.3 mg/dL. Her electrocardiogram showed prolong QTc interval of 520 milliseconds (compared with 445 milliseconds on her previous electrocardio- gram). Her creatinine was elevated to 3.3 mg/dL. Other laboratory value included sodium of 140 mmol/L, potassium of 3.0 mml/dL, chloride of 107 mmol/dL, carbon dioxide of 17 mmol/dL, phosphorus of 5.4 mg/dL, and PTH of 778 pg/mL. She was diagnosed prerenal acute kidney injury on top of CKD along with denosumab-induced severe hypocalcemia. She was treated with aggressive intravenous (IV) fluid along with IV Calcium gluconate. Her creatinine return to baseline of

1.7 mg/dL, and her ionized calcium level went up to 4.3 mg/dL after 4 days of hospitalization.

Denosumab is a human monoclonal antibody to the receptor activator of nuclear factor-?B ligand, which inhibits the activation of RANK receptor and thus reduces a signal that is essential for development and activity of osteoclasts. Its efficacy to reduce the risk of fracture in women with osteoporosis and to prevent skeletal- related events in patients with bone metastases was proved in large randomized controlled trials [1-4]. Hypocalcemia, although was not observed in the osteoporotic study, was found in the studies of patient with bone metastases. The incidence ranged from 5.5% to 13%, although the decreases in serum calcium were generally mild, transient, and did not require treatment with IV calcium. A subsequent pharmacokinetics and pharmacodynamics study of 55 patients with various degrees of Renal impairment also reported a 15% incidence of hypocalcemia. The incidence was highest among the moderate to severe CKD and the end-stage renal disease group. Only 1 case of hypocalcemia was reported in mild CKD group and none of the patients with normal kidney function. Only 2 patients developed severe hypocalcemia requiring hospitalization for IV calcium gluconate, both of whom had severe CKD [5].

Why patients with CKD are at higher risk for developing

hypocalcemia is not well understood. It is thought to be a pharmacodynamic effect because pharmacokinetic study on denosu- mab does not show any difference of concentration-time profiles based on kidney function [5]. It has been hypothesized that patient with CKD are more dependent on PTH-mediated bone turn-over and inhibition of osteoclastic activity results in a “hungry bone-like syndrome” [6,7].

Although the product monograph does not recommend dose adjustment in patient with renal impairment [8], hypocalcemia was observed in a significant portion of patients with CKD in clinical trials as well as well case report. Our case, again, demonstrates this potentially life-threatening adverse effect. More importantly, our

0735-6757/$ – see front matter (C) 2013

patient developed severe hypocalcemia in the light of moderate CKD, which was not found in the previous report [5]. As the utility of denosumab expands, physicians must be aware of this potentially fatal adverse effect, even with patients with moderate degree of renal insufficiency.

Patompong Ungprasert MD Wisit Cheungpasitporn MD

Narat Srivali MD Wonngarm Kittanamongkolchai MD

Edward F. Bischof MD

Department of Internal Medicine Bassett Medical Center and Columbia University College of Physicians and Surgeons Cooperstown, NY 13326, USA

E-mail address: [email protected] http://dx.doi.org/10.1016/j.ajem.2012.11.011

References

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