CaseCommunity Report Report Prolonged zoledronic acid-induced hypocalcemia in hypercalcemia of malignancy Shraddha Narechania, MD,a Nirosshan Tiruchelvam, MD,a Chetan Lokhande, MD,b Gaurav Kistangari, MD,c and Hamed Daw, MDd aDepartment of Internal Medicine, bOutcomes Research, cDepartment of Hospital Medicine, and dDepartment of Hematology and Oncology, Fairview Hospital, Cleveland, Ohio oledronic acid is a parenteral long-acting value, <2 pmol/L), PTH of 10 pg/ml (normal range, bisphosphonate that has been shown to 15-65 pg/ml), creatinine of 1.1 mg/dL, and creati- Zbe more efective than other bisphospho- nine clearance of approximately 65 ml/min (normal nates in treating hypercalcemia of malignancy. It is range, 88-128 ml/min). Testing for her vitamin D important to be aware of its ability to induce pro- level was not done. longed and severe hypocalcemia (hypoCa) follow- Te patient received treatment with intravenous ing administration, which can be difcult to con- (IV) fuids, calcitonin, and a single 3.3-mg dose of trol despite aggressive calcium replacement. We IV zoledronic acid. After 6 days of treatment, her report on a patient with metastatic breast cancer calcium levels decreased to 12.1 mg/dL, and she was who presented with severe symptomatic hypoCa discharged home. She received her frst session of after receiving zoledronic acid for hypercalcemia of palliative chemotherapy a week after her discharge. malignancy. Two weeks after the zoledronic acid treatment, the patient presented to the hospital with diarrhea as Case presentation and summary well as tingling and numbness all over the body. A A 51-year-old woman was diagnosed with right- physical examination of the patient was remarkable sided breast cancer in 2012 for which she under- for carpopedal spasm of her upper extremities. Te went mastectomy and adjuvant chemoradiation. results of her lab tests were signifcant for a calcium In 2013, she was found to have metastases to the level of 5.2 mg/dL, corrected level of 6.8 mg/dL, axial skeleton, liver, and the left adrenal gland. She ionized calcium of 0.74 mmol/L, magnesium of 1.1 was scheduled to receive palliative chemother- mg/dL (normal range, 1.7-2.6 mg/dL), and potas- apy with docetaxel, trastuzumab, and pertuzumab. sium of 2 mmol/L (normal range, 3.5-5 mmol/L). Her medical history was signifcant for chronic Her serum 25-hydroxy vitamin D level was 5.9 ng/ renal insufciency, gastroesophageal refux disease, ml (normal range, 8-15 ng/ml), consistent with and nephrolithiasis. Her surgical history was sig- severe vitamin D defciency; her PTHrP was 2.2 nifcant for partial parathyroidectomy for primary pmol/L; and her PTH was 180 pg/ml, all of which hyperparathyroidism. was suggestive of secondary hyperparathyroidism Before the patient could be started on any che- owing to vitamin D defciency and hypoCa. Te motherapy treatment for her metastatic cancer, she results of an ECG showed sinus tachycardia and presented to the emergency department with poly- low voltage throughout but the corrected QT inter- uria, generalized weakness, and lethargy. Her physi- val was normal. cal examination was unremarkable. Laboratory tests Te patient was started on a continuous IV cal- were done, and she was found to have hypercalce- cium infusion after being given 2 grams of IV cal- mia of malignancy with a calcium level of 22 mg/dL cium and was monitored in the intensive care unit. (normal range, 8.5-10.5 mg/dL). Her other labora- She required 6-12 g of IV calcium daily in addition tory values included elevated parathyroid hormone- to high doses of oral calcium (up to 3.375 g) and related protein (PTHrP) of 14 pmol/L (reference repletion of potassium and magnesium during her Accepted for publication August 3, 2015. Correspondence: Shraddha Narechania, MD; [email protected]. Disclosures: The authors have no disclosures. JCSO 2015;13:374-377. ©2015 Frontline Medical Communications. DOI 10.12788/jcso.0166. 374 THE JOURNAL OF COMMUNITY AND SUPPORTIVE ONCOLOGY g October 2015 www.jcso-online.com Narechania et al ZA was given Pamidronic acid was given Last follow-up 25 a 5 Numerical value of electrolytes 1 6/28/17 7/28/17 8/28/17 9/28/17 10/28/17 Date Calcium (mg/dL) PTH (pg/ml) PTHrP (pmol/l) Magnesium (mg/dL) Potassium (mmol/l) FIGURE Electrolyte abnormalities in the patient. PTH, parathyroid hormone; PTHrP, parathyroid hormone-related protein; ZA, zoledronic acid aY-axis denotes numerical values of electrolytes in their respective units. hospital stay. She was discharged home on 5 g IV calcium, calcemia are multiple, the most common being humoral 100 mEq of potassium chloride, and 2 g magnesium daily, hypercalcemia of malignancy owing to the production of along with 50,000 units of vitamin D 3 times a week. She PTHrP by cancer cells. Other mechanisms include osteo- required that supplementation for 28 days after she was dis- lytic metastases, which causes increased bone resorption by charged, after which her calcium levels were replete. After osteoclasts, and production of calcitriol by tumor cells.7,8 4 weeks of of calcium and vitamin D supplementation, she Management of hypercalcemia of malignancy includes presented again with hypercalcemia of malignancy (Ca of aggressive hydration with IV f uids, combined with agents 16.6 mg/dL) and with a PTHrP level of 44 pmol/L. She such as calcitonin. Bisphosphonates are often indicated was given pamidronic acid 60 mg IV; this time she did not for patients with symptomatic or severe (serum calcium, develop hypoCa because her vitamin D levels were replete. >14 mg/dL) hypercalcemia. T e results from 2 large, dou- ble-blind, randomized, controlled trials demonstrated that Discussion zoledronic acid was superior to pamidronate in terms of Several cases of severe hypoCa after bisphosphonate ef cacy and safety for the treatment of hypercalcemia of administration have been reported.1-5 To our knowledge, malignancy,9 which later led to its approval by the US Food this is the f rst case reported in literature showing severe and Drug administration for treatment of hypercalcemia def ciency of calcium, magnesium, and potassium requir- of malignancy. T e common adverse ef ects associated ing IV and oral supplements for a prolonged period after with the use of zoledronic acid include f u-like symptoms the administration of zoledronic acid for hypercalcemia of , including fever, myalgia, arthralgia and malaise, gastroin- malignancy. testinal ef ects, and renal insuf ciency. Hypercalcemia of malignancy is a potentially life-threat- Bisphosphonates have a similar structure to that of ening complication seen most commonly in patients with pyrophosphate and attach to hydroxyapatite sites on the breast cancer, lung cancer, and multiple myeloma, and it bone and inhibit osteoclast-mediated bone resorption in portends a poor prognosis.6 T e mechanisms of hyper- a variety of ways.10 Bisphosphonates have multiple uses Volume 13/Number 10 October 2015 J THE JOURNAL OF COMMUNITY AND SUPPORTIVE ONCOLOGY 375 Case Report in clinical practice, including the treatment of osteopo- and malnutrition. Of note, a retrospective study of 120 rosis, multiple myeloma, bone metastases, and hypercal- patients who had received zoledronic acid infusions dem- cemia of malignancy. Intravenous bisphosphonates have onstrated symptomatic hypocalcemia in 8% of the patients 100% bioavailability, have a faster onset of action, and have despite their having received appropriate dosing and sup- the advantage of lesser gastrointestinal side efects unlike plementation of vitamin D and calcium before infusion.20 oral bisphosphonates such as alendronate. Zoledronic acid Hypomagnesemia was found in all patients with hypoCa is one of the most potent bisphosphonates (it is at least a in that study. hundred times more potent in inhibiting bone resorption Kreutle et al recommend checking calcium, phosphate, in preclinical studies) when compared with pamidronate sodium, potassium, phosphate, and magnesium a week after acid.1,11 It is administered as an IV infusion over a short bisphosphonate use, at least for the frst time, and followed time of 5-15 minutes, which makes it preferable to other by subsequent checks every few months.2 Te side efects of IV bisphosphonates. bisphosphonates are frequently underestimated in clinical However, bisphosphonates also afect mobilization of practice but they can have a signifcant efect on patient qual- calcium and cause hypoCa. Tis side efect is exacerbated in ity of life. For example, patients may require IV replacement patients who are clinically predisposed to hypoCa because of electrolytes at home for a long time, which will afect qual- of other factors such as vitamin D defciency, hypomag- ity of life. Tere have also been reports of seizures occurring nesemia, hypoparathyroidism, or renal insufciency.12-14 in patients who are on bisphosphonates owing to electrolyte It is also exacerbated in patients with osteoblastic bony disturbances.21,22 For that reason, it is important to be aware metastases because of increased calcium uptake by osteo- of the side efects and to take the necessary measures to pre- blasts.15 Te body’s normal response to counteract hypoCa vent them. Tis will help in preventing unnecessary hospital- is to increase secretion of PTH, which in turn increases the izations and reducing costs of care. renal absorption of calcium, increases production of vita- min D to increase intestinal reabsorption of calcium, and Conclusions increases serum calcium levels. Tis response is blunted in Tis report highlights the serious adverse efect of pro- patients with pre-existing vitamin D defciency as in the longed and sometimes life-threatening hypocalcemia as a current case, and these patients are prone to hypoCa.16 result of bisphosphonate therapy in hypercalcemia of malig- In patients with renal insufciency, tubular dysfunction nancy.