Osteonecrosis of the Jaw in Association with Targeted Therapy

Fig. 18.1

Molecular mechanisms of action of denosumab, bevacizumab and sunitinib in bone physiology and angiogenesis in comparison to bisphosphonates (Reprinted from Troeltzsch et al [7] with kind permission of The Canadian Dental Association)

Denosumab

The indications for denosumab use are similar to those of bisphosphonates [10, 14], and their clinical use has been advocated and increased in recent years [15]. Although denosumab in general displays a low-toxicity profile [16], various well-designed randomized studies have proven the significance of denosumab in the etiology of ONJ [15, 1723] (Table 18.1). Denosumab-related osteonecrosis of the jaw (DRONJ) is reported at a similar rate as BRONJ [15, 1721]. This is remarkable, as denosumab and bisphosphonates have significantly different mechanisms of action [16]. The risk of ONJ development after denosumab exposure seems to rise with increased denosumab doses and reduced application intervals [16]. Unlike bisphosphonates, denosumab is not incorporated into the bone matrix and has a shorter tissue half-life [14, 16]. In contrast to bisphosphonates which take effect in all cell lines, denosumab is targeted against the RANKL-RANK system controlling osteoclast differentiation [10]. Osteoclasts originate from the monocyte-macrophage cell lineage and exert immunologic functions [7, 9, 24, 25]. It is unclear whether the reduction of bone turnover or the inhibition of immunological processes, which can be induced by denosumab, is the decisive step in the development of DRONJ [25]. More research will be necessary to elucidate this matter.

Table 18.1

Relevant randomized controlled trials investigating the risk of DRONJ development compared to the risk of BRONJ development
 
BRONJ rate/examined patients receiving bisphosphonates
DRONJ rate/examined patients receiving denosumab
Reason for drug use
Stopeck et al. [15]
2.0 %/1,020
1.6 %/1,026
Metastatic breast cancer
Henry et al. [17]
1.3 %/878
1.1 %/878
Various malignancies with lytic bone disease
Fizazi et al. [19]
1 %/951
2 %/950
Disseminated prostate cancer
Kyrgidis et al. [23]
1.5 %/1,914
1.3 %/1,908
Bone metastases of various cancers
Bone et al. [21]
N/A
0.13 %/4,550
Osteoporosis in postmenopausal women
Henry et al. [18]
0.8 %/792
1.1 %/786
Bone metastases of solid tumors
Saad et al. [22]
1.3 %/2,860
1.8 %/2,862
Bone metastases of solid tumors and patients with multiple myeloma
Scagliotti et al. [20]
0.8 %/395
0.7 %/406
Bone metastases in lung cancer patients

Bevacizumab

Bevacizumab is a human monoclonal antibody inhibiting blood vessel formation with applications in the treatment of breast, ovarian, lung, renal, central nervous, and colon cancer as well as in the treatment of macular degeneration which received approval of the American Food and Drug administration (FDA) in 2004 [7, 12, 26, 27]. The antineoplastic effect of bevacizumab is enhanced when administered in combination with conventional chemotherapy drugs when compared to isolated bevacizumab therapy [12]. Common side effects of bevacizumab employment are hypertension, thromboembolic events, gastrointestinal perforations, and wound healing complications [12]. Bevacizumab as an addition to chemotherapy regimens may increase the frequency and severity of these side effects [28].
A possible association between ONJ etiology and bevacizumab was reported recently [7, 24]. The implications of bevacizumab in the etiology of ONJ are unclear. The limited number of reported bevacizumab-associated ONJ cases raises considerable doubt whether bevacizumab alone can cause ONJ [7, 29]. Until 2012, 55 cases of bevacizumab-associated ONJ had been reported to the British and French drug regulatory agencies in a cohort of 800,000 patients in therapy [30]. There is clinical suspicion that the simultaneous application of bevacizumab and bisphosphonates increases the risk of ONJ development and leads to spontaneous, sometimes multilocular, ONJ lesions [8, 28, 31, 32]. A considerable amount of cases have been reported in the literature [26, 27, 29, 3339] (Table 18.2). In most of those cases, bevacizumab was administered as part of a complex chemotherapeutic regimen, and dentoalveolar surgical procedures had not been performed [27, 29, 33, 35, 37, 38]. Although bisphosphonates and bevacizumab decrease the bone blood supply, ONJ lesions usually exhibit an intact vascular architecture [7, 14, 29, 40, 41]. On the other hand, there are reports of the importance of VEGF for osteoclast activity [42]. VEGF increases osteoclastic bone resorption and is therefore essential in the control of bone turnover [42]. Furthermore, the presence of VEGF triggers immunologic processes [42]. Limited bone turnover and debilitated immunologic response in combination with soft tissue toxicity by small vessel breakdown [43] may create a scenario in which ONJ can develop. It is therefore conceivable that bevacizumab is associated with ONJ, and precautions should be undertaken before the performance of dentoalveolar surgeries in these patients [7].

Table 18.2

Compilation of reported cases of bevacizumab-related ONJ until December 2013; only cases of ONJ development in patients who never received bisphosphonates are listed
 
Number of reported cases
Reason for bevacizumab administration
Circumstances of ONJ development
Estilo et al. [27]
2
Breast cancer
Unclear, no dentoalveolar surgeries performed
Greuter et al. [35]
1
Breast cancer
ONJ development after tooth extraction
Serra et al. [36]
1
Lung cancer
ONJ development after tooth extraction
Guarneri et al. [37]
2
Disseminated colon, breast, and renal cancer
N/A
Disel et al. [33]
1
Colon cancer
Unclear, no dentoalveolar surgeries performed
Hopp et al. [26]
1
Intravitreal injection for the treatment of retinal vein thrombosis
Unclear, no dentoalveolar surgeries performed
Santos-Silva et al. [29]
1
Renal cancer
Unclear, no dentoalveolar surgeries performed
Sato et al. [38]
1
Colon cancer
Unclear, no dentoalveolar surgeries performed
Pakosch et al. [34]
1
Pancreatic carcinoma
Mandibular abscess surgical drainage
Brunamonti et al. [39]
1
Adenocarcinoma of the parotid gland
Pericoronitis of mandibular wisdom tooth

Sunitinib

Sunitinib belongs to the group of small-molecule multikinase inhibitors [44]. The main effect of sunitinib is the inhibition of receptor tyrosine kinases with implications in neoangiogenesis [44]. The exact molecular mechanism of action of sunitinib is very complex as it blocks multiple intracellular signaling pathways at the same time [44, 45]. Macrophage maturation, mobility, and maturation may be impeded by sunitinib effects such as antagonism on M-CSF (macrophage-colony stimulating factor, Fig. 18.1) [7, 24]. Therefore, an inhibition of macrophage function by sunitinib is conceivable [24]. Sunitinib was approved by the FDA in 2007 and is administered orally [45]. The range of application for sunitinib comprises gastrointestinal stromal tumors (GIST), neuroendocrine tumors, and advanced renal cell cancer [4447]. The main side effects of sunitinib application are mucositis, thrombocytopenia, neutropenia, gastrointestinal symptoms, and fatigue [44].
Several case reports of ONJ development in patients treated with sunitinib alone or in combination with other chemotherapy regimens have surfaced since 2009 (Table 18.3) [8, 13, 32, 4654]. At the present time, there is very little evidence that sunitinib therapy alone may be associated with an increased risk for ONJ development [7, 50, 51]. The British and French drug regulatory agencies registered 27 cases of sunitinib-associated ONJ in a cohort of 100,000 patients receiving sustained sunitinib treatment until the end of 2012 [30]. However, there is considerable evidence that patients receiving chemotherapy, bisphosphonates, and sunitinib at the same time are at a higher risk to develop ONJ [7, 8, 13, 32, 46, 48, 49, 52, 53]. The underlying reasons have yet to be elucidated [24]. Impaired macrophage function, depletion of blood supply, and decay of the epithelial barrier as side effects of sunitinib treatment may contribute to the evolution of ONJ [24, 46].

Table 18.3

Compilation of reported cases of sunitinib-related ONJ until December 2013; cases of ONJ development after sunitinib treatment alone and in combination with BP are listed
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Author
Number of reported cases
Reason for treatment
Bisphosphonate (BP) therapy
Outcome
Brunello et al. [13]
1
Renal cancer
Intravenous BP therapy prior to sunitinib treatment
Healing after surgical intervention and antibiotic treatment
Christodoulou et al. [32]
1
Renal cancer
Intravenous BP therapy prior to sunitinib treatment
Improvement of symptoms after conservative therapy
Bozas et al. [48]
1
Renal cancer
Concurrent treatment with intravenous BP and sunitinib
Healing after BP drug holiday and hyperbaric oxygen treatment
Hoefert et al. [49]
3
Patients 1–3: renal cancer
Patients 1 and 2: concurrent intravenous BP therapy
Patients 1 and 2: healing after discontinuation of sunitinib and surgical/antibiotic therapy
   
Patient 3: previous intravenous BP therapy
Patient 3: healing after two surgical interventions, antibiotic treatment, and discontinuation of sunitinib
Koch et al. [47]
1
Renal cancer
Sunitinib treatment alone
Healing after surgical intervention and antibiotic treatment
Bonacina et al. [50]
3
N/A
Concurrent intravenous BP therapy and sunitinib
N/A
Fleissig et al. [46]
1
Renal cancer
Sunitinib treatment alone
Healing after surgical intervention and antibiotic treatment
Nicolatou-Galitis et al. [51]
1
Nov 4, 2015 | Posted by in General Dentistry | Comments Off on Osteonecrosis of the Jaw in Association with Targeted Therapy
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