• Users Online: 159
  • Print this page
  • Email this page


 
 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 18  |  Issue : 1  |  Page : 7-9

Denosumab in giant cell tumor of bone – science wins over evidence


Department of Orthopaedics, Amala Institute of Medical Sciences, Thrissur, Kerala, India

Date of Submission03-May-2021
Date of Decision20-May-2021
Date of Acceptance30-Jun-2021
Date of Web Publication25-Jul-2021

Correspondence Address:
Dominic Puthoor
Amala Institute of Medical Sciences, Thrissur, Kerala
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joasis.joasis_11_21

Get Permissions

  Abstract 


Denosumab is a relatively new drug and is used in the treatment of giant cell tumor (GCT) of bone. There are hardly any drugs such as denosumab, indication of which changed in a short period of 10 years. The author analyses the cause of this transformation of indication of that drug in the treatment of GCT of bone, based on the scientific ground, review of the literature, and personal experience.

Keywords: Curettage, denosumab, giant cell tumor of bone


How to cite this article:
Puthoor D. Denosumab in giant cell tumor of bone – science wins over evidence. J Orthop Assoc South Indian States 2021;18:7-9

How to cite this URL:
Puthoor D. Denosumab in giant cell tumor of bone – science wins over evidence. J Orthop Assoc South Indian States [serial online] 2021 [cited 2021 Dec 9];18:7-9. Available from: https://www.joasis.org/text.asp?2021/18/1/7/322297




  Introduction Top


Giant cell tumor (GCT) of bone is a benign, osteolytic neoplasm of bone. The receptor activator of NF-KB (nuclear factor kappa-light-chain-enhancer of activated B cells) ligand (RANKL) pathway has been shown to play a key role in the pathogenesis of GCT. Development of monoclonal antibody to RANKL, denosumab, offered promise in the management of these patients. Denosumab was approved for marketing by the European Commission in May 2010. In June 2013, the FDA approved denosumab for the treatment of adults and skeletally mature adolescents with GCT of bone that is unresectable or where resection would result in significant morbidity. Thereafter lots of reports started coming from various parts of the world to the extent that, it was even termed as the wonder drug or golden bullet for GCT of the bone. Situation had come to a stage that the treatment of GCT of bone is going to be medical and surgeons will not have any role in its treatment. Reason is, with Denosumab, GCT which was destroying bone rapidly is not only brought under control, the areas already destroyed are replaced by healthy-looking bone. Histologically also there were amazing changes, giant cells disappeared and there was extensive new bone formation.[1],[2],[3],[4],[5]

Soon, we understood that things are not that bright. Reports start coming showing inevitable recurrence on stopping the drugs. In addition, the recurrence rate in cases treated by curettage after receiving denosumab was found to be very high.[6],[7],[8] Interestingly, one of the earlier reports of the higher rate of local recurrence is from India.[9],[10] To made things worse, there were isolated reports of malignant transformation in case treated with Denosumab. A total of 11 cases of osteosarcoma developed in cases treated by Denosumab was reported till 2018.[11],[12],[13]

What went wrong? If you analyze the pathophysiology of GCT and the scientific basic of the action of Denosumab, we can explain all these [Figure 1]. Giant cell tumor of bone contains not only giant cell but stromal cells also. Stromal cells far outnumber giant cells and are found to be the real culprit behind the disease. It is the stromal cells that recruit monocytes from the circulation and convert them into osteoclasts such as giant cell, which in turn produces lysis of the bone. This is achieved by overexpression of RANKL by the stromal cells. Under their influence monocytes which expresses RANK undergo fusion to from multinucleated giant cells. This is comparable to extremist influencing and recruiting youngsters and making use of them for antisocial activities.
Figure 1: Pathophysiology of GCT of Bone

Click here to view


Denosumab being antibody to RANKL effectively prevents this recruitment process. In that scenario, monocytes are converted into osteoblast causing new bone formation. This explains changes that occur in cases of GCT of bone, treated with Denosumab.

The fact remains that, the real culprit, the big boss, i. e., the stromal cell is not dealt with. Once Denosumab is withdrawn, stromal cells resume its recruitment. This explains the recurrence of lesion when the drug is stopped. Why there is increased rate of recurrence in cases treated by curettage after getting Denosumab? Reason is, tumor cells (stromal cells) remain trapped between the various layers of bone which was formed by the action of Denosumab, making it difficult to assess the extent of the lesion. Even if you do a thorough extended curettage, tumor cells are likely to escape.[14]

The scientific fact, that Denosumab does not have action on stromal cells, was known at the time when approval was given for its use in GCT of bone.[15],[16] However, statistical evidence in various studies suppressed that scientific fact and gave it an aura of magic drug. Cost of single-dose of Denosumab (120 mg) at the time of its launch was 1200 U.S. dollars. It took 5 years for the truth to become accepted. Looking back most of the studies on the beneficial aspect of Denosumab were short-term studies and involve the small number of patients. Funding for most of the studies was from Amgen, Inc.

Situation is comparable to Solu-Medrol (Methylprednisolone Succinate) that was widely used for acute spinal cord injury. Despite the fact it is a steroid, we were forced to use it for decades because of evidence.[17]

Is there any role for Denosumab in the treatment of GCT of bone? Definitely, there is. In the words of Dr. Manish Agarwal, Orthopedic Oncologist from Mumbai, after the peak of inflated expectations, trough of disillusionment and slope of enlightenment, we have come to a stage of Plateau of Productivity.[18] Now, the indications are well defined. No role for Denosumab, for GCT of bone, if you are planning for curettage. There can be exceptions such as sacrum where resection results in gross morbidity. Here, preoperative Denosumab makes the lesion less vascular. The drug can be continued postoperatively also. Now, there is consensus regarding the use of Zoledronic acid instead of Denosumab postoperatively.[18] How long it has to be given is a matter of concern.

Definite indication for the use of Denosumab is, when we plan for resection of the tumor. This drug given preoperatively, make resections a lot easier. You get a nice hard shell from which you can separate the important neurovascular structures. Moreover, it helps to take out the tumor without tumor spillage, thus avoiding chances for local recurrence. This is a big advantage in bones such as the spine, pelvis, proximal radius, and proximal fibula.

Yet another use of Denosumab I found very useful is, when there is soft-tissue recurrence. [Figure 2] shows, X-ray of a case of GCT lower radius treated by resection and ulnar transposition.[19] Later, he presented with soft-tissue recurrence. Because of implant, MRI was not possible. After three doses of Denosumab, soft-tissue recurrence became ossified and became visible in X-ray. Peroperatively, shell resembling eggshell, developed in the periphery of the lesion made its removal easy and complete [Figure 3].
Figure 2: X-ray after denosumab showing bone formation at the site of soft-tissue recurrence

Click here to view
Figure 3: Peroperative photo the same patient

Click here to view


Ethical clearance

The author certifies that he has obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Thomas D, Henshaw R, Skubitz K, Chawla S, Staddon A, Blay JY, et al. Denosumab in patients with giant-cell tumour of bone: An open-label, phase 2 study. Lancet Oncol 2010;11:275-80.  Back to cited text no. 1
    
2.
Chawla S, Henshaw R, Seeger L, Choy E, Blay JY, Ferrari S, et al. Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: Interim analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol 2013;14:901-8.  Back to cited text no. 2
    
3.
Boye K, Jebsen NL, Zaikova O, Knobel H, Løndalen AM, Trovik CS, et al. Denosumab in patients with giant-cell tumor of bone in Norway: Results from a nationwide cohort. Acta Oncol 2017;56:479-83.  Back to cited text no. 3
    
4.
Balke M, Hardes J. Denosumab: A breakthrough in treatment of giant-cell tumour of bone? Lancet Oncol 2010;11:218-9.  Back to cited text no. 4
    
5.
Kyrgidis A, Toulis K. Safety and efficacy of denosumab in giant-cell tumour of bone. Lancet Oncol 2010;11:513-4.  Back to cited text no. 5
    
6.
Errani C, Tsukamoto S, Leone G, Righi A, Akahane M, Tanaka Y, et al. Denosumab may increase the risk of local recurrence in patients with giant-cell tumor of bone treated with curettage. J Bone Joint Surg Am 2018;100:496-504.  Back to cited text no. 6
    
7.
Tsukamoto S, Tanaka Y, Mavrogenis AF, Kido A, Kawaguchi M, Errani C. Is treatment with denosumab associated with local recurrence in patients with giant cell tumor of bone treated with curettage? A systematic review. Clin Orthop Relat Res 2020;478:1076-85.  Back to cited text no. 7
    
8.
Errani C, Tsukamoto S, Mavrogenis AF. How safe and effective is denosumab for bone giant cell tumour? Int Orthop 2017;41:2397-400.  Back to cited text no. 8
    
9.
Agarwal MG, Gundavda MK, Gupta R, Reddy R. Does denosumab change the giant cell tumor treatment strategy? Lessons learned from early experience. Clin Orthop Relat Res 2018;476:1-10.  Back to cited text no. 9
    
10.
Chinder PS, Hindiskere S, Doddarangappa S, Pal U. Evaluation of local recurrence in giant-cell tumor of bone treated by neoadjuvant denosumab. Clin Orthop Surg 2019;11:352-60.  Back to cited text no. 10
    
11.
Tsukamoto S, Righi A, Vanel D, Honoki K, Donati DM, Errani C. Development of high-grade osteosarcoma in a patient with recurrent giant cell tumor of the ischium while receiving treatment with denosumab. Jpn J Clin Oncol 2017;47:1090-6.  Back to cited text no. 11
    
12.
Broehm CJ, Garbrecht EL, Wood J, Bocklage T. Two cases of sarcoma arising in giant cell tumor of bone treated with denosumab. Case Rep Med 2015;2015:767198.  Back to cited text no. 12
    
13.
Aponte-Tinao LA, Piuzzi NS, Roitman P, Farfalli GL. A high-grade sarcoma arising in a patient with recurrent benign giant cell tumor of the proximal tibia while receiving treatment with denosumab. Clin Orthop Relat Res 2015;473:3050-5.  Back to cited text no. 13
    
14.
Traub F, Singh J, Dickson BC, Leung S, Mohankumar R, Blackstein ME, et al. Efficacy of denosumab in joint preservation for patients with giant cell tumour of the bone. Eur J Cancer 2016;59:1-2.  Back to cited text no. 14
    
15.
Lau CP, Huang L, Wong KC, Kumta SM. Comparison of the anti-tumor effects of denosumab and zoledronic acid on the neoplastic stromal cells of giant cell tumor of bone. Connect Tissue Res 2013;54:439-49.  Back to cited text no. 15
    
16.
Mak IW, Evaniew N, Popovic S, Tozer R, Ghert M. A translational study of the neoplastic cells of giant cell tumor of bone following neoadjuvant denosumab. J Bone Joint Surg Am 2014;96:e127.  Back to cited text no. 16
    
17.
Dominic Puthoor. Be aware of your scientific background and be proud of it. President's Theme 2015. Kerala J Orthp 2016;28:2-3.  Back to cited text no. 17
    
18.
Global Perspective of Denosumab in GCT – The Yellow Ribbon-7 PM-11July. Available from: https://www.youtube.com/watch?v=Jr3wiovoTKA&feature=youtu.be. [Last accessed on July 2020 Jul 11].  Back to cited text no. 18
    
19.
Puri A, Gulia A, Agarwal MG, Reddy K. Ulnar translocation after excision of a Campanacci grade-3 giant-cell tumour of the distal radius: An effective method of reconstruction. J Bone Joint Surg Br 2010;92:875-9.  Back to cited text no. 19
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
References
Article Figures

 Article Access Statistics
    Viewed348    
    Printed0    
    Emailed0    
    PDF Downloaded34    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]