Seizures Associated with Zoledronic Acid for Osteoporosis

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Zoledronic acid is a potent iv aminobisphosphonate used in the treatment of osteoporosis (1, 2), Paget's disease of bone, and skeletal metastases (3). The com-.
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Seizures Associated with Zoledronic Acid for Osteoporosis Elena Tsourdi,* Tilman D. Rachner,* Matthias Gruber, Christine Hamann, Tjalf Ziemssen, and Lorenz C. Hofbauer Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III (E.T., T.D.R., M.G., C.H., L.C.H.), and Division of Neurology (T.Z.), Technical University Medical Center, D-01307 Dresden, Germany; and Center of Regenerative Therapies (L.C.H.), D-01307 Dresden, Germany

Context: Bisphosphonates represent potent antiresorptive drugs that are established for therapy of patients with benign and malignant bone diseases. Zoledronic acid is an iv aminobisphosphonate that is administered annually against osteoporosis. Because of its potency and the parenteral route of administration, zoledronic acid is an alternative to oral bisphosphonates, in particular in elderly patients with multiple comorbidities. The most common side effects include an acute-phase reaction and mild and transient hypocalcemia. Objective: Here, we report three cases of seizures that developed after the administration of zoledronic acid. Methods: We review case histories and laboratory results of three patients with seizures associated with the administration of zoledronic acid. We discuss their course and comorbidities in the context of the published literature. Results: All three patients were elderly persons with multiple comorbidities, including neurological diseases, that required parenteral bisphosphonates for severe osteoporosis with concurrent contraindications for oral bisphosphonates. Conclusion: We analyze potential mechanisms underlying these seizures in association with zoledronic acid exposure and discuss potential strategies to minimize this risk. (J Clin Endocrinol Metab 96: 1955–1959, 2011)

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oledronic acid is a potent iv aminobisphosphonate used in the treatment of osteoporosis (1, 2), Paget’s disease of bone, and skeletal metastases (3). The combination of its high affinity to hydroxyapatite and its potent inhibition of the osteoclastic key enzyme farnesyl pyrophosphate synthase translate into a yearly parenteral treatment regimen for osteoporosis. The parenteral route of administration circumvents the poor adherence associated with oral bisphosphonates and the potential gastrointestinal side effects. Combined with its high efficacy to reduce the risk of vertebral and nonvertebral fractures, zoledronic acid is a reasonable option for elderly patients with comorbidi-

ties and those who do not tolerate or absorb oral bisphosphonates. Side effects associated with the use of zoledronic acid include a transient and self-limiting acute-phase reaction, in particular during the first administration, mild to moderate hypocalcemia, and mild and transient renal impairment (1, 2). Some of these side effects can be minimized by adequate calcium and vitamin D supplementation, generous rehydration, and discontinuation of drugs that potentiate renal toxicity, such as diuretics. In the osteoporosis setting, rare cases of osteonecrosis of the jaw with an incidence of 1:100,000 to 1:10,000 (4) and subtrochanteric or diaphyseal femur fractures with an incidence of 2.8 per

ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2011 by The Endocrine Society doi: 10.1210/jc.2011-0418 Received February 16, 2011. Accepted March 28, 2011. First Published Online April 20, 2011

* E.T. and T.D.R. contributed equally. Abbreviation: DXA, Dual-energy x-ray absorptiometry.

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10,000 person-years (5) have been associated with zoledronic acid therapy. Here, we report on three patients with osteoporosis who developed seizures after the administration of zoledronic acid. We review their history and comorbidities, discuss potential mechanisms, and outline strategies for minimizing this risk.

Patients and Methods All patients presented to the Bone Clinic of the Technical University Medical Center, a tertiary referral hospital for osteoporosis. A comprehensive history and physical examination assessed risk factors for osteoporosis, falls, comorbidities, and medications. Laboratory evaluation included a complete blood count, renal and liver function tests, bone-specific alkaline phosphatase activity, and serum levels of calcium, phosphate, sodium, potassium, glucose, PTH, and 25-hydroxyvitamin D. In addition, thyroid function tests, serum protein electrophoresis, and free testosterone levels (in men only) were measured. Bone mineral density was measured using DXA Lunar Prodigy from General Electric (GE Lunar Corp., Madison, WI) at the lumbar spine and the femoral neck by an experienced densitometry nurse. Radiographs of the lumbar and thoracic spine were performed to detect silent vertebral fractures. Calcium and vitamin D supplementation was immediately initiated, and the patients were informed about the benefits and risks associated with the administration of zoledronic acid. Six to 8 wk after the initial evaluation, zoledronic acid was administered in a standardized fashion. All patients were advised to drink adequately 2 d before and to consume a light meal. Five milligrams of zoledronic acid were infused over a period of 45 min using an automated volumetric pump, which was followed by a 500-ml infusion of 0.9% of saline.

Case presentation Case 1 An 80-yr-old woman with postmenopausal osteoporosis had a history of localized gastric cancer treated with total gastrectomy 5 yr earlier (Table 1). Since then she had repeatedly experienced mild hypoglycemic episodes that were managed by advising her to consume frequent and small meals. Her past anti-osteoporosis medication included raloxifene for 3 months, and she was currently taking a calcium/vitamin D supplement. Her laboratory assessment (Table 2) was remarkable for mild hypocalcemia of 2.14 mmol/liter and an elevated C-reactive pro-

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tein concentration of 13.2 mg/liter. Her baseline 25-hydroxyvitamin D level was 20.2 ng/ml, and her PTH level was 48 pg/ml. Dual-energy x-ray absorptiometry (DXA) measurement confirmed osteoporosis with a T score of ⫺4.1 at the lumbar spine and of ⫺2.6 at the total hip. In light of poor gastrointestinal absorption, parenteral treatment with zoledronic acid was recommended, and the patient received 1000 mg of calcium carbonate and 1000 IU of vitamin D per day. Two months later, zoledronic acid was administered with the patient in the supine position. Thirty minutes after starting the infusion, she reported symptoms consistent with an aura (lightheadedness, dizziness, lip smacking) and developed a tonicclonic seizure with a 5-min loss of consciousness. Zoledronic acid infusion was stopped, and a blood glucose level of 1.6 mmol/ liter was measured. There was no indication of blood pressure dysregulation. The patient was administered parenteral glucose (40 ml of 40% glucose) and recovered promptly. There were no indications of tongue biting, urinary incontinence, or a postictal status. The patient admitted that she was so excited about getting the “osteoporosis shot” that she skipped a meal. It was assumed that hypoglycemia after total gastrectomy caused a hypoglycemic seizure. The remaining zoledronic acid was administered after the patient had taken a light meal. Since then, two subsequent annual infusions have been administered without complications when the patient followed our advice to avoid fasting before the zoledronic acid infusion. According to her wish, she was then switched to denosumab at 60 mg every 6 months.

Case 2 A 75-yr-old female patient presented with glucocorticoid-induced osteoporosis. She had previously suffered from an ACTHproducing pituitary adenoma and hypercortisolism that had required two transsphenoidal surgeries and radiotherapy, finally rendering her with partial anterior pituitary insufficiency that required hydrocortisone (30 mg/d) and levothyroxine (50 ␮g/d). In addition, she had been prescribed levetiracetam (3 g/d) after sustaining a primary focal, secondary generalized seizure with status epilepticus 6 months before (Table 1). DXA assessment revealed a T-score of ⫺2.5 at the lumbar spine, and an x-ray demonstrated a vertebral fracture of the third lumbar spine. Supplementation with 1000 mg of calcium carbonate and 1000 IU of vitamin D per day was started. Three months later, she was hospitalized for a urinary tract infection with a C-reactive protein of 10.4 mg/liter (Table 1). At that point, her serum calcium level was 2.23 mmol/liter, basal 25-hydroxyvitamin D level was 20.6 ng/ml, and PTH level was 34 pg/ml. After she had recovered following appropriate iv antibiotic therapy as well as fluid and hydrocortisone replacement, this occasion was used to administer zoledronic acid.

TABLE 1. Characteristics of three patients with seizures after zoledronic acid therapy Case

Gender/ age (yr)

T score (LS/FN)

Fractures

Prior osteoporosis therapy

1

F/80

⫺4.1/⫺2.6

None

2

F/75

⫺2.5/⫺0.8

VF L3

Calcium carbonate 1 g/d, vitamin D 1000 IU/d, raloxifene 60 mg/d Calcium carbonate 1 g/d, vitamin D 1000 IU/d

3

M/84

⫺3.2/⫺3.6

None

Calcium carbonate 1 g/d, vitamin D 1000 IU/d, alendronate 70 mg/wk

Medications

Comorbidities

Time lag to seizure (h)

None

Total gastrectomy

Hydrocortisone, amlodipine, aspirin, fentanyl, levothyroxine, pantoprazole, levetiracetam Valsartan, hydrochlorothiazide, diclofenac, topiramate

Urinary tract infection, seizure, arterial hypertension

48

Partial gastrectomy, stroke, seizures, arterial hypertension

24

LS, Lumbar spine; FN, femoral neck; VF, vertebral fracture; L3, third lumbar spine; F, female; M, male.

0.5

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TABLE 2. Laboratory and endocrine profile of three patients with seizures after zoledronic acid therapy Case

Calcium (mmol/liter)

Phosphate (mmol/liter)

Sodium (mmol/liter)

Glucose (mmol/liter)

25-(OH)-D (ng/ml)

PTH (pg/ml)

GFR (ml/min)

CRP (mg/liter)

WBC (Gpt/liter)

1 2 3 Reference range

2.14 2.23 2.31 2.19 –2.54

0.89 0.76 1.21 0.87–1.45

140 147 134 136 –145

1.60 7.63 9.87 3.50 –5.60

20.2 20.6 23.9 ⬎30

48 34 26 11– 67

70 84 41 ⬎75

13.2 10.4 3.5 ⬍5.0

7.62 8.95 10.79 3.8 –9.8

25-(OH)-D, 25-Hydroxyvitamin D; GFR, glomerular filtration rate; CRP, C-reactive protein; WBC, white blood cell count.

The next day, the patient became febrile (39.2 C) and the day after, developed a seizure and briefly lost consciousness. Serum calcium and glucose levels were normal. Under the assumption of a febrile seizure, she was transferred to the intensive care unit and received iv antibiotics (piperacillin and tazobactam) and ample fluid resuscitation. She also briefly required vasopressor support with norepinephrine but rapidly recovered. She did not return to our Bone Clinic and was lost to follow-up.

Case 3 An 84-yr-old man presented with a history of partial gastrectomy (Billroth II) 58 yr earlier and two ischemic strokes (17 and 10 yr before) leading to blindness and left hemiplegia (Table 1). The patient had a history of chronic seizures that had developed after the last stroke (10 yr earlier) but were well-controlled with topiramate (100 mg/d), and he had not had an epileptic episode for several months under the current therapy. The patient had several risk factors for falls, including blindness, hemiplegia, and chronic immobilization, but reported no clinical fractures. DXA measurement revealed T-scores of ⫺3.2 at the lumbar spine and ⫺3.6 of the femoral neck. The patient had regularly taken 1000 mg of calcium carbonate and 1000 IU of vitamin D per day but had not tolerated oral alendronate. Laboratory evaluation revealed impaired renal function with a glomerular filtration rate of 41 ml/min, mild hyperkalemia, and a slightly elevated white blood cell count, a normal serum calcium level of 2.31 mmol/ liter, a mildly reduced 25-hydroxyvitamin D level of 23.9 ng/ml, and a normal PTH level of 26 pg/ml (Table 2). He had arterial hypertension, but his blood pressure was well controlled. In light of the high risk of osteoporotic fractures and falls, he agreed to receive iv zoledronic acid. The infusion of zoledronic acid was well tolerated. However, 24 h later the patient experienced a tonic-clonic seizure followed by a prolonged loss of consciousness. When evaluated in the emergency room, the patient had normal calcium and glucose serum levels and normal blood pressure, and renal function was not further impaired. He rapidly regained his consciousness and recovered. Six months later, he suffered a hip fracture and underwent hip replacement. Postoperatively, he had a minor seizure while on his regular antiepileptic medication. He is now in a nursing home and requires a wheelchair.

Discussion Bisphosphonates are potent antiresorptive drugs, and a number of large studies have shown unquestionable benefits to patients with diseases characterized by excessive bone resorption. Currently, two options of applying bisphosphonates are available, oral or paren-

teral. Zoledronic acid represents a highly potent iv aminobisphosphonate that is effective in various benign and malignant metabolic bone diseases. In the osteoporosis setting, its parenteral route of administration confers a high adherence, in particular in those patients who do not adhere to or tolerate oral bisphosphonates. The most common side effects include an acute-phase reaction, hypocalcemia, and renal toxicity. We present three cases of seizures in association with the administration of zoledronic acid for osteoporosis. Our patients shared two features: 1) chronic medical conditions that favored a parenteral over an oral bisphosphonate; and 2) all had preexisting neurological diseases, including a history of seizures. In fact, two of the three were receiving anticonvulsants. Seizures are common disorders in the elderly, with a lifetime risk of 3.6% and a substantial increase in incidence after the age of 60 yr. The cause of seizures may be idiopathic or may result from an underlying lesion of the central nervous system, including vascular, traumatic, developmental, infectious, neoplastic, and degenerative causes (6). Despite the wide use of bisphosphonates, thus far, only two cases of seizures have been reported in association with the administration of bisphosphonates. One case reported a seizure in a 92-yrold woman with a positive history of focal epilepsy who received alendronate for osteoporosis (7). The second case described a grand mal seizure in an 87-yr-old man receiving zoledronic acid to prevent skeletal-related events in metastatic prostate cancer (8). In both studies, hypocalcemia was thought to represent the underlying mechanism of lowering the seizure threshold because the patients’ symptoms normalized rapidly after correction of serum calcium levels. In our small case series, all patients had serum calcium levels that were low or in the lower normal range, and their vitamin D serum levels were slightly over 20 ng/ml (Table 2), despite taking a vitamin D/calcium supplement. After the seizures, the vitamin D supplement doses were increased to 20,000 IU once per week in all three patients. Patients 1 and 3 had had prior gastric surgery. Gastrectomy affects pancreatic and enteric hormones that regulate glucose homeostasis. Postoperatively, the

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dumping syndrome could trigger hypoglycemia and seizures. In addition, impaired absorption of calcium and vitamin D along with a lack of postprandial suppression of bone turnover due to alterations of pancreatic and enteric hormone homeostasis may contribute to low bone mass (9). Total gastrectomy may have predisposed patient 1 to hypoglycemic episodes, another risk factor for seizures. After nutritional counseling to consume frequent small meals, two subsequent zoledronic acid infusions could be administered without neurological or other side effects. As a consequence, we check serum glucose levels in all patients with gastrectomy before zoledronic acid is infused. Patient 2 was hospitalized and had just recovered from a severe urinary tract infection with persistent systemic signs of infection as evidenced by the elevated white blood cell count. For practical and logistical reasons, we elected to administer iv zoledronic acid at the end of her hospital stay. It is possible that the acute-phase reaction that is associated with a proinflammatory cytokine milieu and activation of ␥␦ T cells overlapped with the resolving infection and triggered a febrile seizure. Moreover, it is a well-known fact that fever lowers the seizure threshold (10). Although from the patient’s perspective it may be convenient to receive zoledronic acid infusion for osteoporosis when hospitalized for another reason, this may enhance the risk of side effects, in particular in the presence of infections and inflammatory disorders. Thus, we now postpone zoledronic acid infusion until the patient has made a full recovery, has been discharged, and is able to attend the outpatient clinic. As a tertiary referral center, most of our patients suffer from secondary osteoporosis or have various comorbidities associated with postmenopausal osteoporosis that preclude straightforward treatment regimens. This may represent a negative selection bias toward overestimating the relevance of seizure after zoledronic acid infusion. Our patients are mostly elderly, frail patients in whom drug interactions and medication side effects are common and in whom oral anti-osteoporosis drugs do not work. Therefore, they may benefit mostly from an effective antiresorptive therapy while being most prone to adverse reactions related to this treatment. The diagnosis of epilepsy requiring chronic therapy with antiepileptic drugs represents a risk factor for low bone mass and osteoporotic fractures (11). Thus, these patients may be increasingly treated with bisphosphonates, underscoring the relevance of these findings. Our case series does not indicate that zoledronic acid per se caused the seizures. The incidence of seizures after zoledronic acid should be assessed in larger study populations and high-risk cohorts, e.g. after an ischemic stroke.

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Based on our limited personal experience, we suggest adhering to the following clinical recommendation when considering zoledronic acid therapy in elderly patients with a history of seizure. Adequate calcium and vitamin supplementation is mandatory to prevent hypocalcemic episodes that may lower the seizure threshold. Patients prone to hypoglycemic seizures should have their glucose levels checked and eat a light meal before the infusion. We advise against zoledronic acid shortly after a systemic infection because this may trigger a febrile episode, another cause of a seizure. These may be simple, but effective measures to prevent rare, yet potentially life-threatening reactions in high-risk patients that are in great need for a potent therapy against osteoporosis.

Acknowledgments Address all correspondence and requests for reprints to: Lorenz C. Hofbauer, M.D., Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technical University Medical Center, Fetscherstrasse 74, D-01307 Dresden, Germany. E-mail: [email protected]. The research program of L.C.H. is supported by Deutsche Forschungsgemeinschaft grants HO 1875/8-1, HO 1875/12-1, and HO 1875/13-1. This manuscript contains parts of the medical thesis from E.T. at Dresden Technical University Medical School. Disclosure Summary: L.C.H. has received honoraria from Amgen, Merck, Novartis, and Nycomed. E.T., T.D.R., M.G., C.H., and T.Z. have nothing to disclose.

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