SEIZURES ASSOCIATED WITH ZOLEDRONIC ACID THERAPY: A CASE REPORT AND REVIEW OF LITERATURE

Abstract

Objective: Seizures following administration of potent bisphosphonates have been reported only sporadically in medical literature. The rare cases described were often attributed to other precipitating factors such as hypoglycemia, acute infection or predisposition to post-bisphosphonate hypocalcemia. We review the previous cases and present a new case of suspected seizure episode following Zoledronic Acid therapy.
Methods: We describe a case of a 63-year-old woman with a history of well controlled epileptic disorder with no seizure activity in recent years. She was treated with intravenous Zoledronic Acid due to osteoporosis. Twelve hours after treatment, she suffered an episode of loss of consciousness with urinary incontinence suspected to be seizure-related.
Results: Unlike previously reported cases, our patient had a low risk for post-infusion hypocalcemia as her creatinine, calcium, parathyroid hormone and Vitamin D were all within normal limits prior to the infusion.
Conclusions: Our interpretation of the scenario described is based on clinical judgment and not supported by ancillary studies. Nevertheless, our case, along with the limitations described, joins other reports, and raises questions about possible interaction between a convulsion disorder and a potent bone resorption inhibition administration, leading to a relative hypocalcemia and possible seizure threshold reduction. This question should be further explored by other studies.

Full text

DOI:10.4158/ACCR-2020-0234
© 2020 AACE.
AACE Clinical Case Reports Rapid Electronic Articles in Press
Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and
accepted for publication, but have yet to be edited, typeset and finalized. This version of the
manuscript will be replaced with the final, published version after it has been published in the
print edition of the journal. The final, published version may differ from this proof.
DOI:10.4158/ACCR-2020-0234
© 2020 AACE.
Case Report ACCR-2020-0234
SEIZURES ASSOCIATED WITH ZOLEDRONIC ACID THERAPY: A CASE REPORT AND
REVIEW OF LITERATURE
Roy Shalit M.D., M.P.H1, Liana Tripto-Shkolnik M.D 1,2
Running title: Seizures associated with Zoledronic acid therapy
From: Division of Endocrinology, Diabetes and Metabolism, Chaim Sheba Medical
Center, Tel-Hashomer, Ramat Gan, Israel1, Sackler Faculty of Medicine, Tel Aviv
University, Tel Aviv, Israel2
Running title: Seizures associated with Zoledronic acid therapy
Corresponding address: Dr. Roy Shalit
Division of Endocrinology, Diabetes and Metabolism,
Chaim Sheba Medical Center, Tel-Hashomer.
Derech Sheba 2 St. Ramat Gan, Israel. 5265601.
Email: Rshalit@gmail.Com

DOI:10.4158/ACCR-2020-0234
© 2020 AACE.
Abstract
Objective: Seizures following administration of potent bisphosphonates have been reported
only sporadically in medical literature. The rare cases described were often attributed to other
precipitating factors such as hypoglycemia, acute infection or predisposition to post-
bisphosphonate hypocalcemia. We review the previous cases and present a new case of
suspected seizure episode following Zoledronic Acid therapy.
Methods: We describe a case of a 63-year-old woman with a history of well controlled
epileptic disorder with no seizure activity in recent years. She was treated with intravenous
Zoledronic Acid due to osteoporosis. Twelve hours after treatment, she suffered an episode of
loss of consciousness with urinary incontinence suspected to be seizure-related.
Results: Unlike previously reported cases, our patient had a low risk for post-infusion
hypocalcemia as her creatinine, calcium, parathyroid hormone and Vitamin D were all within
normal limits prior to the infusion.
Conclusions: Our interpretation of the scenario described is based on clinical judgment and
not supported by ancillary studies. Nevertheless, our case, along with the limitations
described, joins other reports, and raises questions about possible interaction between a
convulsion disorder and a potent bone resorption inhibition administration, leading to a
relative hypocalcemia and possible seizure threshold reduction. This question should be
further explored by other studies.
Abbreviations;
ZA = Zoledronic Acid; IV = intravenous; EEG = electroencephalogram; IU = international units;
BMD = bone mineral density; DXA = Dual-energy X-ray absorptiometry; CTX = C-terminal
telopeptide; PTH = parathyroid hormone; P1NP = procollagen type 1 N-terminal propeptide.

DOI:10.4158/ACCR-2020-0234
© 2020 AACE.
Introduction:
Zoledronic acid (ZA ( , is a high potency heterocyclic imidazole bisphosphonate. It inhibits bone
resorption efficiently by reducing the activity and inducing apoptosis of osteoclasts (1).Another
important effect is the ability of ZA to inhibit tumor cell invasion, possibly via inhibition of bone
matrix-degrading proteinases (2). Due to its high potency ZA is indicated and widely used for the
treatment of bone metabolic diseases, including osteoporosis, osteogenesis imperfecta, Paget disease of
bone or for management of malignant hypercalcemia, associated with multiple myeloma and other
solid malignancies(3).
ZA is generally well-tolerated, with flu-like reaction being the most common immediate side effect
occurring in up to 30 percent of patients. Other side effects include gastrointestinal symptoms, transient
low-grade fever, arthralgia and bone pain. Hypocalcemia has been reported in patients treated with
intra-venous (IV) ZA, ranging from mild asymptomatic to severe life-threatening hypocalcemia
involving cardiac arrhythmias and neurologic adverse events (seizures, tetany, and numbness).
Therefore the United States Food and Drug Administration agency instructs that hypocalcemia must be
corrected before initiating ZA, by adequately supplementing patients with calcium and vitamin D (3).
Less common serious adverse reaction such as osteonecrosis of the jaw, atypical femoral fractures have
also been described. The post infusion decline of ZA concentrations in plasma is a triphasic process
with rapid decrease from peak concentration at the end of infusion to less than 1% of the concentrations
maximum within 24 hours, and prolonged terminal elimination phase, with measured concentrations in
plasma between Days 2 and 28 post infusion, and a terminal elimination half-life of 146 hours (3).
Seizures after the administration of bisphosphates have been reported in only 5 cases in the medical
literature (4-6), mostly in patients with other precipitating factors, such as hypoglycemia, acute
infection or predisposition to post-bisphosphonate hypocalcemia. (7). Hypocalcemia is a well-known
precipitating cause of seizures in patients with convulsive disorders (8).
A case:
A 63-year-old woman was evaluated for osteoporosis in our department. She reported a history of
epilepsy diagnosed during her 30's. The diagnosis was made after she suffered a "grand mal" tonic –
clonic seizure. She was initially prescribed Valproic acid and Carbamazepine, which were later
substituted with Levetiracetam and Sultiame. With the latter regimen her seizures were well-controlled,
and she had not had any seizures for several years. She completed 48 hours video EEG 2 months before
the ZA treatment and neither clinical nor electrophysiological epileptic activity was noted.
The patient was diagnosed with multiple myeloma with elevated serum Immunoglobulin-G monoclonal
pick (lambda chain predominance), and hyper cellular bone marrow with 10-15 % plasma cells. She
had neither myeloma skeletal lesions nor hypercalcemia, and no hematological or renal compromise.
Her disease was classified as smoldering myeloma and required no active treatment.
She also had dyslipidemia well controlled with statin and ezetimibe therapy.
The patient was compliant with her medications that included; 600 mg of calcium carbonate and 400

DOI:10.4158/ACCR-2020-0234
© 2020 AACE.
international units (IU) of vitamin D, 75 mg of aspirin, 50 mg of Sertraline ,5 mg of Rosuvastatin
calcium -,and 10 mg per day Ezetimibe, Sultiame 200 mg/ bd and Levetiracetam 1000 mg/bd .
As part of a workup following myeloma diagnosis, a bone mineral density (BMD) by Dual-energy X-
ray absorptiometry (DXA) was performed. The measurement revealed T-scores of −2 at the lumbar
spine and −1.6 at the left femoral neck.
Fracture history included a broken ankle after a car accident several years before. She sustained several
fractures after a fall from her bicycle: a hairline costal fracture involving ribs 4-6 and an L4 vertebral
compression fracture. The mentioned fall from the bicycle was not judged clinically as a major trauma,
because by her description it happened during a slow bicycle ride without any major acceleration force
on the impact.
Laboratory evaluation was unremarkable, a normal serum calcium level of 9.17 mg/dl (2.29 mmol/l), a
normal 25-hydroxyvitamin D level of 95.2 nmol/l (38.14 ng/ml), and a normal parathyroid hormone
(PTH) level of 18.6 pg/ml (10-65 pg/mL), glucose 91 mg/dl (5.05 nmol/l) normal renal function with
an estimated glomerular filtration rate of 62 ml/min, pretreatment bone markers revealed C-terminal
telopeptide (CTX) of 710 pg/ml (normal postmenopausal 556-1108 pg/ml) and procollagen type 1 N-
terminal propeptide (P1NP) of 71.6 ng/ml (normal postmenopausal 30-58 pg/ml ).
Due to an estimated high risk for osteoporotic fractures, (multiple myeloma, relatively high CTX,
previous fracture) the decision was to treat her with an IV ZA.
The infusion of ZA was administered in the ambulatory setting with no immediate side effects. The
night (about 12 hours) after the infusion, the patient reported dizziness and generalized weakness
followed by loss of consciousness with urinary incontinence, she was later found by her daughter,
regained consciousness and did not seek medical help.
The incident was reported during her scheduled appointment in the endocrinology and neurology
clinics, the working diagnosis was an epileptic seizure suspected to be related to the ZA infusion. The
patient was advised against future treatment with IV bisphosphonates or another potent antiresorptive
agent, denosumab.
In the following 3 years the patient had a normal EEG and did not experience any clinical seizures and
did not sustain fractures. The bone resorption marker declined, as expected, with CTX levels;
165,208,230 pg/ml on each of the following years respectively, with no specific osteoporosis treatment
other than continued calcium and vitamin D supplementation.
Discussion:
After reviewing the medical literature, we found 5 reported cases of seizures occurring soon after a
bisphosphonates administration, 4 of them after ZA use. In 2011 Tsourdi et al. described three cases of
seizures after the administration of ZA (Table 1, cases 1-3) (6), another case was reported by
Navarro et al. 2007 (5); and a case of seizures during treatment with oral alendronate described
by Maclsaac et al. 2002 (4) (Table 1, cases 4 and 5 respectively) . In all previous reports predisposing
factors were present and were discussed elaborately by Das RR(7) . In cases 1 and 2 the predisposing

DOI:10.4158/ACCR-2020-0234
© 2020 AACE.
factor was presumed to be hypoglycemia (potentiated by prior gastric surgery leading to a dumping
syndrome). In case 3, the patient developed a febrile seizure on the second day of ZA administration,
given during a systemic and a central nervous system infection requiring iv antibiotics and vasopressor
support.
In cases 4 and 5, pre-treatment hypocalcemia was thought to represent the predisposing factors for the
seizures development. Notably all previously discussed patients (cases 1-5) had pre-existing vitamin D
deficiency, which is a well-known risk factor for bisphosphonates-induced hypocalcemia and has even
been previously reported to result in severe life-threatening and symptomatic hypocalcemia (9, 10).
Similarly, a case of serious hypocalcemia and multiple seizures, developing after the first treatment
with Denosumab in a 83-year-old woman has been described (11). The hypocalcemia associated with
potent antiresorptive agents was suggested to be a result of reduced calcium efflux from bone, which is
normally followed by a transient period of slight hypocalcemia and a compensatory increase in PTH
hormone secretion, distal renal tubular reabsorption of calcium and enhanced intestinal calcium
absorption through increased renal production of 1,25-dihydroxyvitamin D (1, 12-15).Therefore
metabolic states that impair these compensatory mechanisms including hypomagnesemia,
hypoparathyroidism, renal dysfunction, and vitamin d deficiency can potentially cause hypocalcemia
after bisphosphonate (or other potent antiresorptive) use.
Das et al. concluded in his paper that no clear direct cause -and-effect relationship between
bisphosphonates administration and seizures was evident by the clinical data of cases 1-5 (Table 1) and
suggested, that any disturbances of mineral metabolism (calcium, magnesium) should be corrected
before IV bisphosphonates administration (7).
We described a case of self-reported episode of loss of consciousness suspected to be an epileptic
seizure, a major limitation of our case study is the fact that our patient did not seek immediate medical
attention after suffering the episode and hence our interpretation of the scenario described is based on
clinical judgment and not supported by ancillary studies. With this major limitation in mind, the
episode occurred in a patient with well-controlled epilepsy that had no clinical seizures or syncope in
recent years, nor had she suggested epileptic activity in a recent EEG test. The episode occurred less
than 24 hours after the ZA infusion and was described by the patient subjectively similar to the
previous epileptic seizures she suffered. The patient did not report a head trauma, fever, chest pain or
any clinical complaints suggesting secondary causes of loss of consciousness. Unlike previously
reported cases; pre-treatment calcium and vitamin d levels as well as the kidney function were within
normal range (Table 1), thus mineral metabolism abnormality as the precipitating factor for the seizure
was thus unlikely. Based on the limited reports, Tsourdi et al. suggested checking and correcting
metabolic abnormalities prior to bisphosphonate infusion, in order to decrease seizure episode risk,
including adequate calcium and vitamin d supplementation to prevent hypocalcemia, normalization of
glucose levels, and postponing treatment in patients with systemic infection since this may trigger a
febrile seizure episode(6).

DOI:10.4158/ACCR-2020-0234
© 2020 AACE.
Although all the above suggested measures have been undertaken, our patient sustained an episode
suspected to be a seizure in a close proximity to a potent IV bisphosphonate infusion. The causal
connection between seizures and IV ZA is unproven. We believe that our case, along with the
limitations described, joins other rare reports, and raises questions about possible interaction between a
convulsion disorder and a potent bone resorption inhibition administration, leading to a relative
hypocalcemia and possible seizure threshold reduction. We do not claim causality, and further studies
are needed in order to better explore the relationship between parenteral bisphosphonates, and possible
seizure threshold reduction.
REFERENCES
1. Roelofs AJ, Thompson K, Ebetino FH, Rogers MJ, Coxon FP. Bisphosphonates: molecular
mechanisms of action and effects on bone cells, monocytes and macrophages. Curr Pharm Des.
2010;16:2950-60.
2. Clezardin P. Anti-tumour activity of zoledronic acid. Cancer Treat Rev. 2005;31 Suppl 3:1-8.
3. FDA (NPCp. ZOMETA(R)) intravenous injection concentrate, zoledronic acid intravenous injection
concentrate. Product Information. East Hanover, NJ: 2016.
4. Maclsaac RJ, Seeman E, Jerums G. Seizures after alendronate. J R Soc Med. 2002;95:615-6.
5. Navarro M, Lopez R, Alana M, et al. Tonic-clonic seizure as the presentation symptom of severe
hypocalcemia secondary to zoledronic acid administration. J Palliat Med. 2007;10:1226-7.
6. Tsourdi E, Rachner TD, Gruber M, Hamann C, Ziemssen T, Hofbauer LC. Seizures associated with
zoledronic acid for osteoporosis. J Clin Endocrinol Metab. 2011;96:1955-9.
7. Das RR. Seizure associated with zoledronic Acid therapy: side-effects or coincidental finding? Ther
Adv Endocrinol Metab. 2011;2:169-70.
8. Han P, Trinidad BJ, Shi J. Hypocalcemia-induced seizure: demystifying the calcium paradox. ASN
Neuro. 2015;7.

DOI:10.4158/ACCR-2020-0234
© 2020 AACE.
9. Rosen CJ, Brown S. Severe hypocalcemia after intravenous bisphosphonate therapy in occult
vitamin D deficiency. N Engl J Med. 2003;348:1503-4.
10. Stiff PJ, Tanvetyanon T. Management of the adverse effects associated with intravenous
bisphosphonates. Annals of Oncology. 2006;17:897-907.
11. Rodriguez-Gomez D, Lustres-Perez M, Rodríguez-Noguera M, Perez-Carral V, Fernandez-Regal I.
Hypocalcemia with encephalopathy and epileptic seizures secondary to treatment with denosumab.
Revista de neurologia. 2015;60:189-90.
12. Chennuru S, Koduri J, Baumann M. Risk factors for symptomatic hypocalcaemia complicating
treatment with zoledronic acid. Internal medicine journal. 2008;38:635-7.
13. Kreutle V, Blum C, Meier C, et al. Bisphosphonate induced hypocalcaemia - report of six cases and
review of the literature. Swiss Med Wkly. 2014;144:w13979.
14. Papapoulos SE, Harinck HI, Bijvoet OL, Gleed JH, Fraher LJ, O'Riordan JL. Effects of decreasing
serum calcium on circulating parathyroid hormone and vitamin D metabolites in normocalcaemic and
hypercalcaemic patients treated with APD. Bone Miner. 1986;1:69-78.
15. Maalouf NM, Heller HJ, Odvina CV, Kim PJ, Sakhaee K. Bisphosphonate-induced hypocalcemia:
report of 3 cases and review of literature. Endocrine Practice. 2006;12:48-53.

DOI:10.4158/ACCR-2020-0234
© 2020 AACE.
Table 1 –Reported cases of seizures occurring after IV bisphosphonates administration- demographics,
medical therapy, seizure risk factors and lab work
Case
(reference)
1(6)
2(6)
3(6)
4(5)
5(4)
Current
report
Gender/age
F/80
M/84
F/75
M/87
F/92
F/64
T score
(LS/FN)
−4.1/−2.6
−3.2/−3.6
−2.5/−0.8
N/A
-3.9/-4
-2/-1.6
Prior
fractures
None
None
VF- L3
MTS-bones
VF- L3
VF- L4
Prior OP
therapy1
raloxifene
60 mg/d
None
None
N/A
AL 10
mg/d
None
Medications
None
Valsartan,
Thiazide,
Diclofenac,
Topiramate
Hydrocortisone,
Amlodipine,
Aspirin, Fentanyl,
Levothyroxine,
Pantoprazole,
Levetiracetam
Bicalutamide,
Leuprolide
Phenytoin
Levetiracetam
Ospolot,
aspirin,
Sertraline,
crestor,
ezetrol
PTH
48
26
34
235
454
18.7
Calcium
2.14
2.31
2.23
2.07
1.89
2.29
Vit-d
20.2
23.9
20.6
5.2
6.4
38.1
Glucose
1.6
9.87
7.63
N/A
N/A
5.05
Seizure
timing post
IV BIS
0.5 hours
after ZA
24 hours
after ZA
48 hours after ZA
96 hours after
ZA
6 weeks
after AL
12 hours after
ZA
Risk factors
for seizures
Total
gastrecto
my,
Hypoglyce
mic
episodes
Partial
gastrectomy
, Stroke,
Seizure
disorde
Transsphenoidal
surgery,
radiotherapy,
partial pituitary
insufficiency
Seizure disorder
Advanced
cancer with
bone MTS
Cerebral
meningio
ma,
Seizure
disorder
Seizure
disorder
1 All patients were treated with supplemental vitamin d3 and calcium carbonate.
IV, intra-venous; F, Female; M, Male; LS, Lumbar spine; FN, femoral neck; N/A, not- available; VF, vertebral
fracture; L#, Lumbar spine number; MTS, bone metastasis; OP, osteoporosis; mg/d, milligrams per day;
mg/wk,, milligrams per week; AL, Alendronate; ASA, acetylsalicylic acid. PTH, parathyroid hormone; Vit-d, 25
OH -Vitamin D; GLU, Glucose; ZA, Zoledronic Acid; AL, Alendronate;
Lab values: Vit-d (ng/ml), PTH (pg/ml), Calcium (mmol/liter), Glucose (mmol/liter).