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Tetany: Possible adverse effect of
bevacizumab
Original
Article
Anwikar SR, Bandekar MS, Patel TK1, Patel PB1, Kshirsagar NA
Department of Infectious Diseases, Maharashtra University of Health Sciences, Mumbai, 1Department
of Pharmacology, Govt. Medical College, Bhavnagar, India
Correspondence to: Dr. N A Kshirsagar, E-mail: [email protected]
Abstract
BACKGROUND: Bevacizumab a recombinant humanized monoclonal antibody was approved in 2004 by US FDA for
metastatic colorectal cancer. It is reported to cause potentially serious toxicities including severe hypertension, proteinuria,
and congestive heart failure. AIM: To correlate adverse event tetany with the use of bevacizumab. MATERIALS AND
METHODS: World Health Organization’s Uppsala Monitoring Centre, Sweden, for reporting of adverse drug reactions
from all over the world, identified 7 cases with tetany-related symptoms to bevacizumab from four different countries.
These 7 patients reported to UMC database developed adverse events described as musculoskeletal stiffness (1), muscle
spasm (1), muscle cramps (1), lock jaw or jaw stiffness (4), and hypertonia (1), with hypocalcaemia. RESULTS: After
detailed study of the possible mechanism of actions of bevacizumab and factors causing tetany, it is proposed that there
is a possibility of tetany by bevacizumab, which may occur by interfering with calcium metabolism. Resorption of bone
through osteoclasts by affecting VEGF may interfere with calcium metabolism. Another possibility of tetany may be due to
associated hypomagnesaemia, hypokalemia, or hyponatremia. CONCLUSIONS: Tetany should be considered as a one
of the signs. Patient on bevacizumab should carefully watch for tetany-related symptoms and calcium and magnesium
levels for their safety.
Key words: Bevacizumab, adverse effect, tetany, serum calcium
Introduction
Tetany is the spontaneous tonic muscle contractions
due to increased neuronal excitability that occurs as a
result of low ECF calcium concentration that reduces
the threshold for excitation of the neural tissue. [1,2]
Extracellular calcium and magnesium are thought to
affect the local electric field of the membrane near ion
channels such that hypocalcaemia or hypomagnesaemia
reduce the amount of depolarization necessary to induce
an increase in sodium conductance and depolarize
nerve cells. Threshold for development of symptoms
depends on the serum pH, severity of concomitant
hypomagnesaemia, hypokalemia, and hyponatremia. [1]
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DOI:
10.4103/0019-509X.75819
PMID:
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Indian Journal of Cancer | January–March 2011 | Volume 48 | Issue 1
Many diseases including endocrine disorders like
hyperparathyroidism and alkalosis by hyperventilation
can cause tetany. Typical symptoms of tetany include
carpopedal spasm, laryngospasm, and generalized seizures.
During acute decline in serum calcium, generalized tonic
clonic convulsion or laryngospasm may also occur.[1,2]
Chvostek’s and Trousseau’s signs are provocative tests for
diagnosis of latent tetany. Other features of hypocalcemia
include electrocardiographic abnormality like prolonged
QT interval, marked QRS, and ST segment changes
that may mimic acute coronary syndrome. Ventricular
arrhythmias are a rare complication and congestive heart
failure corrected by normalization of serum calcium has
also been reported. [2]
Bevacizumab is a recombinant humanized monoclonal
antibody that binds to and neutralizes the biological
activity of human vascular endothelial growth factor
(VEGF). Bevacizumab inhibits the binding of VEGF to
its receptors, Flt-1 (VEGF 1) and KDR (VEGF 2), on
the surface of endothelial cells. VEGF binding initiates
angiogenesis (endothelial proliferation and formation of
new blood vessels) and is important for reproductive
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Anwikar, et al.: Bevacizumab and tetany
and bone angiogenesis as well. [3] Bevacizumab is an
antiangiogenic drug that has been shown to inhibit
growth of blood vessels (angiogenesis) in tumors. It
has an estimated half-life of 20 days (11-50 days) and
a predicted time to reach a steady state of 100 days at
therapeutic dose. On February 24, 2004, bevacizumab
was approved by US FDA for use in the treatment
of metastatic colorectal cancer. A phase III study of
irinotecan/5-FU/leucovorin with or without bevacizumab
for the initial treatment of advanced colorectal cancer
showed a significant, though moderate, benefit in
median survival (20.3 vs 15.6 months) and progressionfree survival (10.6 vs 6.2 months) for patients receiving
bevacizumab. There is also evidence of biological
activity of bevacizumab in clear-cell renal cancer as
a single agent and in non-small-cell lung cancer and
breast cancer in combination with chemotherapy. It
can cause potentially serious toxicities including severe
hypertension, proteinuria, and congestive heart failure.[4]
We report here 7 cases of tetany in patients receiving
bevacizumab reported to the WHO Uppsala Monitoring
Centre and analyze the biological possibility of
bevacizumab causing tetany.
Materials and Methods
The WHO Collaborating Centre for International Drug
Monitoring, Uppsala, Sweden, received summary clinical
reports of individual suspected cases of adverse reactions
to pharmaceutical products from National centers in
countries participating in the Collaborative program.
Information on the adverse drug reaction data from
the WHO’s Vigiflow database is not homogenous with
respect to origin or likelihood that the pharmaceutical
product caused the adverse reaction. (This information
does not represent the opinion of the WHO).
The analysis of this dataset is performed with the intention
of signal detection. The Bayesian confidence propagation
neural network (BCPNN) method is used to analyze
all reported adverse drug reactions. In this method, IC
value is determined by analyzing all the adverse drug
reactions. Information component (IC) is a measure of
the disproportionality between the observed and expected
reporting of a drug-ADR pair. A positive IC value
indicates that a particular drug ADR pair is reported
more often than expected, based on all the reports in
the database. If the IC value increases over time and IC
025 (lower limit of a 95% credibility interval for IC)
is positive, this is suggestive of an association between
the drug and the adverse reaction. However, clinical
assessment is essential in identification of signal.
The WHO - Uppsala Monitoring Centre, Sweden
combination database identified 7 cases with tetany
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related symptoms from four different countries with IC
1.85 and IC025 of 0.17 for database quarter 2008-2.
All these reports were studied to determine a possible
relationship between bevacizumab and tetany-related
symptoms.
Result
The 7 patients with tetany-related symptoms reported to
the UMC database for quarter 2008-2 have developed
adverse events described as musculoskeletal stiffness (1),
muscle spasm (1), muscle cramps (1), lock jaw or jaw
stiffness (4), and hypertonia (1), with hypocalcemia in
one patient. It is likely that case 7 is duplicate of case
6. Of the seven patients, six are elderly females and one
is male. All seven patients had received bevacizumab.
Coadministered drug with bevacizumab were capecitabine
in three patients, oxaliplatin and dexamethasone in two
patients, epirubicin, docetaxel, cisplatin, cetuximab,
erlotinib, ondansetron, diazepam, oxazepam, metamizole,
clemastine, and tramadol in one patient. In one patient,
the only documented drug was bevacizumab.
Of the seven cases with tetany, muscle stiffness, and
related symptoms, according to WHO classification,
three cases were possibly related and four cases with
causality unclassified to bevacizumab and, by naranjo
algorithm, three cases of possible and four of doubtful
causality to bevacizumab. All these cases were serious,
as they required prolonged hospitalization. The time
from treatment to AE was 28, 13, and 5 days for
the 3 patients. Of the seven cases, three are reported
from clinical trials studies. In each of these patients,
other drugs could have caused the reaction. There is a
report of hypertonia with tramadol in the cases with
co-administered drugs. Hypocalcemia is reported with
cisplatin and oxaliplatin.[4,5] Convulsion is reported with
docetaxel, clemastine, and tramadol.[6-9] Jaw stiffness
and laryngospasm is not reported with any drug. The
outcome is reported as not recovered in two, recovered
in one, unknown in one, and the outcome for three
patients was not mentioned.
Discussion
In ex vivo cultures of embryonic murine metatarsals, a
well-established model of osteoclast recruitment, receptor
activator of nuclear factor for kappa B ligand (RANKL)
and VEGF play a role in osteoclast chemotaxis –
molecular mechanism homing osteoclasts to their future
site of resorption during bone development.[10] VEGF
treatment of purified murine bone marrow osteoclast
precursors directly enhances their survival, differentiation
into mature osteoclasts, and resorptive activity.[11] In
addition, recombinant human VEGF (rhVEGF) acts
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Anwikar, et al.: Bevacizumab and tetany
as a macrophage colony-stimulating factor in osteoclast
induction in osteopetrotic (op/op) mice. [12] VEGF
can upregulate the RANK expression in osteoclast
precursors that is needed for osteoclastogenesis.
Following administration of bevacizumab, young adult
cyanomolgus monkeys exhibited a physical dysplasia
characterized by increase in hypertrophied chondrocytes
and inhibition of vascular invasion of growth plate,
similar to growth plate lesion observed in mice treated
with Flt(1-3)-IgG.[13]
Remodeling of the bone is maintained by a repeated
process of bone resorption and new bone formation,
controlled, respectively by osteoclasts and osteoblasts.
Bone, which contain 99% of the calcium present in
the body, acts as an internal reservoir for the body.
Calcium stored in the skeleton can be used as a defense
against hypocalcemia. Parathyroid hormone (PTH)
is responsible for the minute-to-minute regulation of
ECF calcium level. It acts on the kidney to stimulate
calcium reabsorption and on bone to stimulate bone
resorption and the release of calcium store into the ECF
in response to hypocalcemia. PTH (1-34) and c-terminal
PTH-related peptide PTHrP (107-139) has been shown
to induce gene expression of VEGF by osteoblastic
cells. [14] Its expression on osteoblastic cells is upregulated
by osteotropic factors such as 1,25-dihydroxyvitamin
D3 and prostaglandin E2, both are stimulators of bone
resorption. VEGF produced by osteoblasts in response
to these osteotropic factors involved in the stimulation
of osteoclastic bone resorption. [15] VEGF receptor 1
(VEGFR-1) signaling, which regulates angiogenesis, is
essential for osteoclast development.[16]
We would like to propose the possibility of tetany by
bevacizumab, which may occur by interfering with
calcium metabolism. Resorption of bone through
osteoclasts by affecting VEGF may interfere with
calcium metabolism. However, hypocalcemia is
documented in one patient only. Other cases with
tetany-related symptoms have not included the
information on the serum calcium level. Bevacizumab
is reported to cause metabolic disturbances like
hypomagnesemia, hypokalemia, and hyponatremia.[17-19]
Thus, other cause of bevacizumab-related tetany may be
hypomagnesemia, hypokalemia, or hyponatremia.
symptoms and monitor calcium and magnesium levels and
observe for alkalosis, in patients receiving bevacizumab.
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Thus, in conclusion, seven cases with tetany, muscle
stiffness, and related symptoms, while three cases possibly
related and four cases with causality unclassified to
bevacizumab, of serious nature are reported from four
different countries. This adverse drug event should be
considered as a signal with a warning to watch for the
Indian Journal of Cancer | January–March 2011 | Volume 48 | Issue 1
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Source of Support: Nil, Conflict of Interest: None declared.
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