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DENTAL SCIENCE - REVIEW ARTICLE
Year : 2012  |  Volume : 4  |  Issue : 6  |  Page : 410-413  

Bisphosphonates: An update


1 Department of Oral Pathology, Vivekananda Dental College, Thiruchenkodu, Tamil Nadu, India
2 Department of Oral Medicine and Radiology, Vivekananda Dental College, Thiruchenkodu, Tamil Nadu, India
3 Department Of Prosthodontics, Adhiparasakthi Dental College, Thiruchenkodu, Tamil Nadu, India

Date of Submission01-Dec-2011
Date of Decision02-Jan-2012
Date of Acceptance26-Jan-2012
Date of Web Publication28-Aug-2012

Correspondence Address:
Nalliappan Ganapathy
Department of Oral Pathology, Vivekananda Dental College, Thiruchenkodu, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0975-7406.100309

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   Abstract 

Bisphosphonates are used widely for variety of bone condition, most notably IV bisphosphonates in the treatment of metastic bone lesion and oral bisphosphonates for osteoporosis. They constitute a group of drugs capable of modulating bone turnover and reducing its remodeling when an excessive resorption occurs. In the last few years, due to their extensive use, many cases of complications associated with their use have been published. This paper provides recent knowledge on general characteristics of these drugs and their mechanism of action, pathogenesis, as well as their relevance to dentist.

Keywords: Bisphosphonate-associated osteonecrosis, osteonecrosis, osteoporosis


How to cite this article:
Ganapathy N, Gokulnathan S, Balan N, Maheswaran T, Venkatesan. Bisphosphonates: An update. J Pharm Bioall Sci 2012;4, Suppl S2:410-3

How to cite this URL:
Ganapathy N, Gokulnathan S, Balan N, Maheswaran T, Venkatesan. Bisphosphonates: An update. J Pharm Bioall Sci [serial online] 2012 [cited 2021 Jul 29];4, Suppl S2:410-3. Available from: https://www.jpbsonline.org/text.asp?2012/4/6/410/100309

Bisphosphonates constitute a group of drugs capable of modulating bone turnover and reducing its remodeling when excessive resorption occurs. They are increasingly being used in number of bone conditions, including osteoporosis, Paget's disease, and metastatic cancer. As a consequence, the reported cases of bisphosphonates related osteonecrosis of jaw (BONJ) have increased. [1]

In the last few years, there has been increasing awareness of the link between bisphosphonates and osteonecrosis of the jaw. (ONJ). As some dental practitioners may not be familiar with this family of drugs, it is important to discuss the growing range of bisphosphonates and their use so that patients who are of developing ONJ are identified.


   Structure Top


Structurally, bisphosphonates are chemically stable derivatives of inorganic pyrophosphate, a naturally occurring compound in which two phosphate groups are linked by esterification. The short RI chain confers pharmacokinetics and longer R2 chain influences bisphosphonate potency. The resorption ability of the molecule can be increased by adding a chain containing cyclic nitrogen or an aminoterminal group on R2 side [2] [Figure 1]. In humans, inorganic pyrophosphate is released as a by-product of many of the body's synthetic reactions, and thus can be readily detected in many tissues including blood and urine. Pioneering studies have demonstrated that inorganic pyrophosphate is capable of inhibiting calcification by binding to hydroxyapatite crystal, leading to the hypothesis that regulation of pyrophosphate level could be the mechanism by which bone mineralization is regulated.
Figure 1: Basic structure of bisphosphonates Simple bisphosphonates Nitrogen-containing bisphosphonates

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   Basic Structure Top


Classification

The newer classification differentiates bisphosphonates into the following groups [Table 1]: Nitrogen containing and non-nitrogen containing. Nitrogen containing bisphosphonates [Figure 2] are more widely used as they are extremely bone selective. For this reason, non-nitrogen containing bisphosphonates are now rarely used. [3]
Figure 2: Chemical structure

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Table 1: Classification of bisphosphonates

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Mechanism of action

The mode of action of bisphosphonates is now more clearly understood. Bisphosphonates have high affinity for calcium ion and so they are strongly attracted to bone. In the resorptive process, bisphosphonates are released from the bone surface and are taken up by osteoclast. In fact, osteoclast can take large amount of bisphosphonates during natural bone resorption.

Protein prenylation is important in osteoclastic activities and for the osteoclast to survive. The mevalonate pathway is central to the prenylation process.

In this pathway, the action of enzyme farnesyl pyrophosphate synthase (FPPS) leads to the production of farnesyl pyrophosphate (FPP) which is necessary for the production of geranyl geranyl pyrophosphate (GGPP) by the action of the enzyme GGPP synthase. FPP and GGPP are both required for prenylation of GTPases. [4] which are signal proteins important for osteoclastic function and survival [Figure 3] and [Figure 4].
Figure 3: Prenylation process

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Figure 4: Action of bisphosphonate[5]

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The bisphosphonate inhibits osteoclastic bone resorption via a mechanism that differs from that of other antiresorptive agents. Bisphosphonate attaches to hydroxyapatite binding site on bony surface, especially surface undergoing active resorption. When osteoclast begins to resorb the bone that is impregnated with bisphosphonate, the BisPhosphonate released during resorption impairs the ability of osteoclast to form ruffled border, to adhere to the bony surface, and to produce the proton necessary for continued bone resorption. [6] Bisphosphonate also reduces osteoclastic activity by decreasing osteoclast progenitor development and recruitment and by promoting osteoclast apoptosis [Figure 5].
Figure 5: Action of nitrogen containing bisphosphonates on osteoclasts

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   Diagnosis of ONJ Top


It is essential to refer ONJ suspected / diagnosed patients, together with a panoramic radiograph (if available) to a specialist. In general dental practice, the working party recommends taking a panoramic radiograph as a good baseline record. Conventional radiographs have limitations. When there are radiopaque sequestra, then radiographically metastatic lesions can be differentiated sufficiently from osteonecrosis. However, if the lesion is osteolytic, radiographs are not useful. Early lesions may also be missed. [7]

The suggested further specialist investigative procedures may include the following.

Bone imaging techniques

  • Computed tomography (CT) used for differential diagnosis.
  • Cone beam CT gives details on thickness of cortex, integrity, and marrow involvement, cancellous bone mineral density (BMD), and irregularities after tooth extraction. [8]
Soft tissue and bone marrow imaging technique

Magnetic resonance imaging (MRI) recognizes ischemic areas with the use of contrasting agents, but it may give false positives.

Functional/physiological tests

  • Technetium-99 radioisotope scintigraphy: In patients with metastatic bone disease, where clinically indicated.
  • Position emission tomography: Not very useful due to poor resolution with high radiation dose.
  • Bone resorption markers such as the collagen telopeptide (CTX) may be of some value in assessing the risk of bisphosphonate-induced osteonecrosis by indicating oversuppression of bone turnover. [9]

   Biopsy Top


In most cases, biopsy is not necessary and may even be detrimental to bone healing. However, when there is a history of parenteral bisphosphonate therapy for metastatic cancer, then the possibility of metastases to the jaw should be seriously considered and, if no biopsy is taken, the reason should be recorded in the patient's notes. [10]

However, there is a need for more research to develop further diagnostic procedures.


   Prevention of ONJ Top


All patients with osteoporosis or other non-malignant disease need good oral hygiene and regular routine dental examinations. There are also important differences in the approach to patients taking bisphosphonates for osteoporosis and non-malignant disease compared to patients with malignancy who are starting or are already taking bisphosphonates. [11],[12] Prevention, wherever possible, is therefore the key. This will have to start at primary care levels. Education and regular updated guidelines for general practitioners are important to limit the impact of ONJ.

 
   References Top

1.Arrain Y, Masud T. Recent Recommendations on Bisphosphonate - Associated Osteonecrosis of the Jaw. Dent Update 2008;35:238-42.  Back to cited text no. 1
    
2.Arrain Y, Masud T. Bisphosphonate and Osteonecrosis of the Jaw-Current Thought. Dent Update 2009;36:415-9.  Back to cited text no. 2
    
3.Russell RG, Watts NB, Ebetino FH, Rogetrs MJ. Mechanisms of action of Bisphosphonates: Similarities and differences and their potential influence on clinical efficiency. Osteoporosis Int 2008;19:733-59.  Back to cited text no. 3
    
4.Fisher JE, Rogers MJ, Halasy JM, Luckman SP, Hughes DE, Masarachia PJ, et al. Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci USA 1999;96:133-8.  Back to cited text no. 4
    
5.Roelofs AJ, Thompson K, Gordon S, Rogers MJ. Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer Res 2006;12:6222-30.  Back to cited text no. 5
    
6.Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action an role in clinical practice. Mayo Clin Proc 2008;83:1032-45.  Back to cited text no. 6
    
7.Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonate induced exposed bone (osteonecrosis/osteopetrosis) of the jaws - risk factors, recognition, prevention and treatment. J Oral Maxillofac Surg 2005;63:1567-75.  Back to cited text no. 7
    
8.Marx RE. Reconstruction of defects caused by bisphosphonate induced osteonecrosis of the jaws. J Oral Maxillofac Surg 2009;67(5 Suppl):107-19.  Back to cited text no. 8
    
9.Marx RE. Oral and Intravenous bisphosphonate induced osteonecrosis of the jaws. History, Etiology, prevention and Treatment. Chicago: Quintessence Publishing Co Inc; 2007. p. 86.  Back to cited text no. 9
    
10.Carlson ER, Basile JD. The role of bisphosphonate - related ostenoecrosis of the jaws. J Oral Maxillofac Surg 2009;67(5 Suppl): 85-95.  Back to cited text no. 10
    
11.Brown JJ, Ramalingam L. Zacharin MR. Bisphosphonate - associated osteonecrosis of the Jaw: Does it occur in children. Clin Endocrinol 2008;68:863-7.  Back to cited text no. 11
    
12.Nancollas GH, Tang R, Phipps RJ, Henneman Z, Gulde S, Wu W, et al. Novel insights into the actions of bisphosphonates on bone; differences in interactions with hydroxyapatite. Bone 2006;38:617-27.  Back to cited text no. 12
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1]


This article has been cited by
1 Antiresorptive Drug–Related Osteonecrosis of the Jaw
Jettie Uyanne,Colonya C. Calhoun,Anh D. Le
Dental Clinics of North America. 2014; 58(2): 369
[Pubmed] | [DOI]



 

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