Zoledronic acid overdose in a two-year-old with osteogenesis imperfecta

Abstract Zoledronic acid is an intravenous (IV) bisphosphonate used to treat bone metastases associated with solid tumors and metabolic bone disorders. It is an established treatment option for children with osteogenesis imperfect (OI). Its efficacy relies on its higher potency and affinity for bone, shorter infusion time, and long-acting kinetics. While therapeutic safety and efficacy have been established, zoledronic acid overdose has been rarely reported. We present a case of a 15-fold zoledronic acid overdose in a 2-year-old child treated for OI requiring pediatric intensive care unit admission. The patient developed hypocalcemia and hypophosphatemia requiring repletion along with ergocalciferol supplementation. He also developed a transient acute phase reaction and electrocardiogram disturbances and underwent hemodialysis. He was discharged on hospital day 12. Zoledronic acid has been associated with electrolyte abnormalities, nephrotoxicity, acute inflammatory responses, metabolic derangements, and arrhythmias. A lack of zoledronic acid concentrations limited our ability to characterize a toxicokinetic profile and precluded an interpretation of the relationship between serum concentrations and clinical effects. Limited clinical experience and literature were available to guide the management of this overdose. Management approach principles should be based on aggressive electrolyte monitoring and supplementation, renal function and cardiac monitoring, and pre-and post-morbid assessment of metabolic parameters. ARTICLE SUMMARY We describe the presentation and management of an overdose of IV zoledronic acid in a pediatric patient.


Introduction
Bisphosphonates are analogs of pyrophosphate, an inhibitor of bone mineralization, used for various bone disorders [1].Therapeutic effects of bisphosphonates include improvements in bone density and mitigation of bone loss [2,3].Zoledronic acid is an intravenous (IV) heterocyclic bisphosphonate used in clinical oncology and endocrinology.It inhibits osteoclast-mediated bone resorption.It is used in children with osteogenesis imperfecta (OI) to reduce the risk of recurrent fractures and bone pain [2].Studies have established the efficacy and safety of zoledronic acid in pediatric patients, yet limited data exist regarding pediatric overdose.We report a case of a two-year-old male who received a 15-fold overdose of zoledronic acid during treatment of OI.

Case
A two-year-old male (10.8 kg), with a history of OI, sustained a right lower leg fracture and was prescribed IV zoledronic acid to increase bone density, reduce pain, and diminish the risk of recurrent fractures.He presented to the hospital for his initial infusion.Pre-treatment laboratory testing two hours prior revealed a normalized ionized calcium, 1.22 mmol/L (reference: 1.12-1.23 mmol/L); serum creatinine, 0.23 mg/dL (reference: 0.2-0.4mg/dL); blood urea nitrogen, 9 mg/dL (reference: 2-20 mg/dL); and phosphorus, 4.7 mg/dL (reference: 3.8-6.5 mg/dL).
The patient was to receive an infusion of 0.27 mg (0.025 mg/kg) zoledronic acid over 50 min, however, he was administered 4 mg (0.37 mg/kg).The error was recognized approximately three hours post-administration, and he was admitted to the pediatric intensive care unit (PICU).Toxicology and nephrology services were consulted.
Upon presentation to the PICU, his vital signs were: heart rate (HR) 122 beats/min; blood pressure 112/79 mmHg; respiratory rate 27 breaths/min; pulse oximetry 100% on room air; and temperature 36.9 °C.The toxicology service recommended calcium, phosphate, magnesium, and creatinine monitoring along with daily supplementation of vitamin D and calcium, which were subsequently performed by the primary treating team.
Daily oral ergocalciferol supplementation with 400 international units was initiated 21 h after zoledronic acid infusion, as well as IV hydration to maintain urine output (Table 1).Oral calcium supplementation was initiated with calcium carbonate 270 mg.Overnight, he developed emesis and was febrile with a rectal temperature of 38.8 °C.Ten hours post-infusion, decreasing serum calcium and phosphate concentrations were observed (Figure 1).Daily calcium supplementation was increased to 1000 mg of 10% IV calcium gluconate 1.7 mMol IV potassium phosphate was added.Total calcium and inorganic phosphate supplementation schedules are outlined in Table 1.
On hospital day (HD) 3, the nephrology service recommended hemodialysis and the patient underwent elective intubation and catheter placement.Hemodialysis was performed on HD 4 with increased supplementation to 2000 mg IV 10% calcium gluconate.He was extubated on HD 4 and continued to receive daily supplemental calcium, inorganic phosphate, and ergocalciferol, with highest calcium and phosphorus requirements on HD 6 (Table 1).No 25-hydroxyvitamin D concentrations were drawn during admission, with a recent value of 45 ng/mL (reference range, 20-50 ng/mL) drawn 44 days prior to treatment.His parathyroid hormone (PTH) concentration was 88 pg/mL 56 h post-infusion; a pre-treatment concentration of 41 pg/mL was drawn 44 days prior (reference range, 10-55 pg/mL).
Oral calcium and inorganic phosphate supplementation were continued from HD 7 until discharge.On HD 7, the patient experienced multiple episodes of limited, asymptomatic, non-sustained ventricular tachycardia, for which no known etiologies, including metabolic derangements, could be identified.His renal function and urine output remained within normal limits during hospitalization.He was discharged on HD 12. Written informed consent for publication of the case details was obtained from the parent.
Upon review of the sequence of events leading to the iatrogenic overdose, the medication was ordered by the endocrinology service.The pharmacy order set verification, however, did not contain built-in pediatric zoledronic acid dosing and therefore was verified based on adult dosing.The medication was prepared based on the incorrect dosing with administration overseen by a general pediatrician and midlevel practitioner, both of whom did not have prior clinical experience with zoledronic acid dosing or administration.

Discussion
This case involved a 15-fold iatrogenic IV zoledronic acid overdose in a child receiving treatment for OI, an inherited bone disorder marked by bone fragility due to decreased type I collagen formation [2].Cyclic IV bisphosphonate therapy, including zoledronic acid, is a recognized treatment for OI due to beneficial effects on bone mineral density by reducing osteoclast activity and inhibiting bone resorption [1,2].While the safety and efficacy of zoledronic acid in pediatric bone disorders are well established, literature on pediatric overdoses is limited.Zoledronic acid is widely used for the management of bone metastases associated with solid tumors, hypercalcemia of malignancy, and various metabolic diseases [1,4].Early clinical experience and literature pertaining to OI treatment primarily describe using disodium pamidronate.Zoledronic acid, however, has been increasingly used and regarded as a safe and effective alternative [1,5].Advantages conferred by zoledronic acid include higher potency and affinity for bone, shorter infusion time, and longer-acting kinetics facilitating less frequent administration [1,2,6].
Bisphosphonate use is associated with hypocalcemia [6].Risk factors for zoledronic acid-induced hypocalcemia include rapid IV administration, premorbid hypovitaminosis D, hypoparathyroidism, and hypomagnesemia [7].These conditions can lead to impaired release and activity of PTH.PTH is responsible for increasing renal calcium and vitamin D absorption as a compensatory mechanism for hypocalcemia caused by decreased skeletal calcium efflux following bisphosphonate treatment [7,8].Hypocalcemia in our patient was likely due to the zoledronic acid overdose.Pre-treatment 25-hydroxyvitamin D and PTH, obtained a month prior, were stable.Further, the elevated PTH concentration post-overdose suggests secondary hyperparathyroidism associated with zoledronic acid-induced hypocalcemia.
Pediatric doses of 0.05 mg/kg produced hypocalcemia in 7-12% of patients, with severe hypocalcemia in ~3%, within three days of infusion [2].Dose reductions from 0.02 to 0.025 mg/kg/dose to 0.0125 mg/ kg/dose in children improved the safety profile and reduced the incidence of hypocalcemia [6].Hypocalcemia secondary to zoledronic acid is reportedly greater in children compared to adults and may reflect more rapid pediatric bone turnover [6].Researchers have advocated for calcium and vitamin D supplementation before and during zoledronic acid infusion [2,6].
Dosing zoledronic acid based on total body weight instead of body mass index (BMI) or body surface area (BSA) may increase risk of exacerbating hypocalcemia [6].Body surface area has been used to calculate dosing regimens of pamidronate for children with OI, but no data currently exist using BSA to dose zoledronic acid.Dosing based on BMI or BSA is limited in children with moderate to severe forms of OI given the difficulty in obtaining accurate height measurements [6,8].
Hypophosphatemia has been shown with zoledronic acid use for hypercalcemia of malignancy [9,10].Bisphosphonate-associated hypophosphatemia likely results from hypocalcemia-induced secondary hyperparathyroidism and inhibition of bone resorption.Although only one PTH concentration was drawn throughout hospitalization, our patient's persistent hypophosphatemia would suggest a similar physiological etiology.
Side effects of zoledronic acid include arthralgia, bone pain, and fever due to release of inflammatory cytokines including tumor necrosis factor-alpha and interleukin-6 [2,6].Elevations in C-reactive protein (CRP) are common in symptomatic patients.Symptoms generally respond to over-the-counter analgesics [2,6].Nephrotoxicity is more severe adverse effect associated with zoledronic acid infusion.Large doses and short infusion times increase the risk of renal injury, including acute tubular necrosis, and renal failure requiring hemodialysis [7].
Zoledronic acid follows triphasic elimination model; an initial plasma half-life of 0.23 h during rapid distribution to tissues, a subsequent half-life of 1.75 h during redistribution to plasma, and a terminal elimination half-life of 167 h due to bone release [11].Approximately 39+/-16% is recovered from the urine, unchanged, in the first 24 h [11].Therefore, intermittent hemodialysis appears unlikely to eliminate clinically significant amounts.
In cases of zoledronic acid overdose, high doses of calcium and phosphate repletion may be necessary.Despite supplementation, our patient became hypocalcemic and hypophosphatemic.Limited clinical data were available to guide treatment.
Limitations of this report include a lack of zoledronic acid concentrations, which preclude an interpretation of kinetics, association of serum concentration and clinical effects, and conclusions on the effectiveness of extracorporeal removal.
This case highlights the "Swiss cheese" model of error whereby failures at multiple levels, as opposed to one specific etiology or root cause, creates harmful errors that reach the patient [12].Pediatric patients are vulnerable to iatrogenic medication dosing errors for myriad reasons, including often requiring weight-based calculations and dosing [12].Preventing such errors requires a multifaceted approach, comprised of strategies that include, but are not limited to -computerized physician order entry with pediatric weight-based dosing calculators and weight-specific maximum and minimum doses; computer-assisted infusion rate calculators; prospective pharmacist tracking systems to improve communication between physicians and pharmacists; barcode medication administration systems to ensure the patient is receiving the correct medication and dose; and, in instance of high-risk IV medications, at least two health professionals verifying the patient's identity, the correct dose, and infusion rate [12].
Pediatric zoledronic acid overdose presents challenges for clinicians due to limited clinical experience and a dearth of literature.Patients may develop electrolyte abnormalities, arrhythmias, and nephrotoxicity.While limited data exist to inform optimal management, pre-and post-infusion investigations are prudent both in the therapeutic and overdose settings.Pre-infusion serum creatinine, calcium, phosphate, vitamin D, and PTH concentrations should be established.Post-infusion parameters should include evaluation for post-infusion reaction, serial electrolyte monitoring and supplementation if necessary, and assessment of urine output and renal function.

Figure 1 .
Figure 1.Patient ionized calcium and phosphate concentrations and repletion pre-and post-zoledronic acid overdose.

Table 1 .
Patient inorganic phosphate and calcium supplementation during hospital course post-zoledronic acid overdose.