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  Table of Contents  
ORIGINAL ARTICLE
Year : 2011  |  Volume : 48  |  Issue : 1  |  Page : 31-33
 

Tetany: Possible adverse effect of bevacizumab


1 Department of Infectious Diseases, Maharashtra University of Health Sciences, Mumbai, India
2 Department of Pharmacology, Govt. Medical College, Bhavnagar, India

Date of Web Publication10-Feb-2011

Correspondence Address:
N A Kshirsagar
Department of Infectious Diseases, Maharashtra University of Health Sciences, Mumbai
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.75819

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 » 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.


Keywords: Bevacizumab, adverse effect, tetany, serum calcium


How to cite this article:
Anwikar S R, Bandekar M S, Patel T K, Patel P B, Kshirsagar N A. Tetany: Possible adverse effect of bevacizumab. Indian J Cancer 2011;48:31-3

How to cite this URL:
Anwikar S R, Bandekar M S, Patel T K, Patel P B, Kshirsagar N A. Tetany: Possible adverse effect of bevacizumab. Indian J Cancer [serial online] 2011 [cited 2017 Nov 23];48:31-3. Available from: http://www.indianjcancer.com/text.asp?2011/48/1/31/75819



 » Introduction Top


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] 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 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 progression-free 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 Top


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 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 Top


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],[7],[8],[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 Top


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 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 D 3 and prostaglandin E 2 , 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],[18],[19] Thus, other cause of bevacizumab-related tetany may be hypomagnesemia, hypokalemia, or hyponatremia.


 » Conclusion Top


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 symptoms and monitor calcium and magnesium levels and observe for alkalosis, in patients receiving bevacizumab.

 
 » References Top

1.Bruder JM, Guise TA, Mundy GR. Mineral metabolism. Endocrine and metabolism. 4th ed. New York McGraw - Hill companies; 2001. p. 1079-177.  Back to cited text no. 1
    
2.Bringhurst FR, Demay MB, Kronenberg HM. Hormons and disorders of mineral metabolism. Williams textbook of endocrinology. 10th ed. USA: Elsevier Science; 2003. p. 1303-73.  Back to cited text no. 2
    
3.Ferrara N, Hillan KJ, Novotny W. Bevacizumab (avstin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 2005;333:328-35.  Back to cited text no. 3
    
4.Chabner BA, Amrein PC, Druker BJ. Antineoplastic Agents. Goodman and Gilman′s the Pharmacologiucal Basis of Therapeutics. 11th ed. New York: McGraw-Hill, Medical Publishing Division; 2006. p. 1315-404.  Back to cited text no. 4
    
5.Takimoto CH, Remick SC, Sharma S. Dose-escalating and pharmacological study of oxaliplatin in adult cancer patients with impaired renal function: A national cancer institute organ dysfunction working group study. J Clin Oncol 2003;21:2664-72.  Back to cited text no. 5
    
6.Docetaxel IV. Available from: http://www.medscape.com/druginfo/dosage?drugid=4890andd rugname=Docetaxel+IV [last cited on 2009 Jan].  Back to cited text no. 6
    
7.Clemastine Oral. Available from: http://www.medscape.com/druginfo/dosage?drugid=7141anddr ugname=Clemastine+Oral [last cited on 2009 Jan].  Back to cited text no. 7
    
8.Tramadol (Tramadol Hydrochloride) - side effects and adverse reactions. Available from: http://www.druglib.com/druginfo/tramadol/side-effects/ [last cited on 2009 Jan].  Back to cited text no. 8
    
9.Gutstein HB, Akil H. Opoid analgesics. Goodman and Gilman′s The Pharmacologiucal Basis of Therapeutics. 11th ed. New York: McGraw-Hill, Medical Publishing Division; 2006. p. 547-90.  Back to cited text no. 9
    
10.Henriksen K, Karsdal M, Delaisse JM, Engsig MT. RANKL and vascular endothelial growth factor (VEGF) induce osteoclast chemotaxis through an ERK1/2-dependent mechanism. J Biol Chem 2003;278:48745-53.  Back to cited text no. 10
    
11.Yang Q, McHugh KP, Patntirapong S. VEGF enhancement of osteoclast survival and bone resorption involves VEGF receptor-2 signaling and beta3-integrin. Matrix Biol 2008;27:589-99.  Back to cited text no. 11
    
12.Kuku M, Kohno S, Kuwata T. Effects of vascular endothelial growth factor on osteoclast induction during tooth movement in mice. J Dent Res 2001;80:1880-3.  Back to cited text no. 12
    
13.Gerber HP, Vu TH, Ryan AM. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med 1999;5:623-8.  Back to cited text no. 13
    
14.Esbrit P, Victoria M, Miguel F. Terminal parathyroid hormone-related protein increases vascular endothelial growth factor in human osteoblastic cells. J Am Soc Nephrol 2000;11:1085-92.  Back to cited text no. 14
    
15.Nakagawa M, Kaneda T, Arakawa T, Morita S, Sato T, Yomada T, et al. Vascular endothelial growth factor (VEGF) directly enhances osteoclastic bone resorption and survival of mature osteoclasts. FEBS Lett 2000;473:161-4.  Back to cited text no. 15
    
16.Niida S, Kondo T, Hiratsuka S, Hayashi S, Amizuka N, Noda T, et al. VEGF receptor 1 signaling is essential for osteoclast development and bone marrow formation in colony-stimulating factor 1-deficient mice. Proc Natl Acad Sci U S A 2005;102:14016-21.   Back to cited text no. 16
    
17.Cooney MM, Garcia J, Brell J. A phase I study of bevacizumab in combination with sunitinib in advanced solid tumors. J Clin Oncol 2007;18:15532.  Back to cited text no. 17
    
18.Bevacizumab IV: Dosage, Uses and Warnings. Available from: http://www.medscape.com [last cited on 2009 Jan].  Back to cited text no. 18
    
19.Cohen MH, Gootenberg J, Keegan P, Pazdur R. FDA drug approval summary: Bevacizumab (Avastin® ) plus carboplatin and paclitaxel as first-line treatment of advanced metastatic recurrent nonsquamous non-small cell lung cancer. Oncologist 2007;12:713-8.  Back to cited text no. 19
    



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