Cancer Treatment Reviews 41 (2015) 455–464

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Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv

Complications of Treatment

Drug induced osteonecrosis of the jaw Issam S. Hamadeh, Bridget A. Ngwa, Yan Gong ⇑ Center for Pharmacogenomics, Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, Fl, United States

a r t i c l e

i n f o

Article history: Received 17 February 2015 Received in revised form 9 April 2015 Accepted 14 April 2015

Keywords: Osteonecrosis of the jaw Bisphosphonates RANKL VEGF Bone remodeling Hydroxyapatite Skeletal related events Osteoporosis

a b s t r a c t Despite the widespread use of bisphosphonates and their unequivocal efficacy for the treatment of various disease states, osteonecrosis of the jaw remains one of the most feared complications associated with their use. Current evidence, however, suggests that there is also a relationship between occurrence of osteonecrosis of the jaw and use of other classes of pharmacotherapies namely RANKL inhibitors as well as angiogenesis inhibitors. Although these drugs have different mechanisms of action than bisphosphonates, they all seem to interfere with the bone remodeling process i.e. alter the balance between bone resorption and bone formation which may be the most plausible explanation for pathogenesis of osteonecrosis of the jaw. The main objective of this review is to introduce the readership to a number of relatively new medications that may cause osteonecrosis of the jaw. Accordingly, we will summarize latest findings from clinical studies, meta analyses and case reports published in medical literature on this topic. For some of these medications, the evidence may not appear as robust as that for bisphosphonates; yet, the possibility of this adverse event occurring with these non bisphosphonate drugs should never be precluded unless proven otherwise. Thus, it is imperative that health care providers implement preventive measures so as to circumvent the incidence of osteonecrosis of the jaw. In this day of age where medical care is becoming personalized, we will highlight some of significant findings from studies seeking to identify genetic markers that may potentially play a role in development of osteonecrosis of the jaw. Ó 2015 Elsevier Ltd. All rights reserved.

Introduction Osteonecrosis of the jaw (ONJ) is a rare but serious disease of the jaw namely the maxilla and mandible. As the name suggests (osteo = bone and necrosis = death), ONJ manifests as lesions of necrotic and exposed bone in the oral cavity that persist for at least 8 weeks. Other accompanying symptoms include pain, mucosal swelling, loose teeth, erythema, and/or infections. Although more than a decade has passed since the first case report of ONJ, the exact pathophysiology of the disease has not been completely elucidated; however several theories have been proposed. ONJ was first introduced in 2003 by Marx RE [1] when he reported 36 cases of ONJ subsequent to the use of intravenous bisphosphonates (zoledronate and pamidronate) for the treatment of hypercalcemia related to multiple myeloma and metastatic breast cancer. The widespread use of bisphosphonates and the seriousness of this condition which adversely impacts the patient’s quality of life, ⇑ Corresponding author at: Center for Pharmacogenomics, Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Box 100484, Gainesville, FL 32610-0486, United States. Tel.: +1 352 273 6297; fax: +1 352 273 6121. E-mail address: [email protected]fl.edu (Y. Gong). http://dx.doi.org/10.1016/j.ctrv.2015.04.007 0305-7372/Ó 2015 Elsevier Ltd. All rights reserved.

prompted Novartis (the manufacturing company of zoledronate and pamidronate) in 2004 to revise the package insert for both drugs so as to alert health care providers about the possibility of the incidence of ONJ with the use of these agents. Moreover, in 2005, this warning was broadened to include oral bisphosphonates indicating that this adverse event is rather a drug class effect. Hence, the term bisphosphonate related osteonecrosis of the jaw (BRONJ) came to light so as to distinguish ONJ caused by bisphosphonates from ONJ of other etiologies. Recently, several case reports have emerged implicating drugs belonging to different therapeutic classes in the pathogenesis of ONJ. Accordingly, the term BRONJ has become obsolete and is no longer restricted to bisphosphonate use. In their latest update of the 2009 position paper on BRONJ [2,3], the American Association of Oral and Maxillofacial Surgeons (AAOMS) recommended that the term BRONJ be replaced with the new terminology ‘‘Medication Related Osteonecrosis of the Jaw’’ (MRONJ) subsequent to this emerging body of evidence. Based on this new position paper, a definitive diagnosis of MRONJ can be made if all of the criteria listed in Table 1 are met. Once identified, the current guidelines provide treatment recommendations on the basis of the severity or stage of the disease (Table 2).

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Table 1 Criteria for diagnosis of medication related osteonecrosis of jaw. Diagnostic criteria based on AAOMS recommendations 1. Current or previous treatment with drugs known to cause ONJ (antiresorptive agents, RANKL inhibitors, VEGFR inhibitors, etc. . .) 2. Exposed bone in the maxillofacial region that has persisted for at least 8 weeks 3. No previous history of radiation to the jaws

With the continued advent of new and complex therapies, the list of drugs associated with ONJ will most likely continue to grow (Table 3). Because staying abreast of drug related complications can be quite daunting, we felt that there is a need for a review paper that recapitulates the most current findings published in the medical literature about this topic. Hence, in this review, we will not only list the drugs implicated in ONJ development, but also describe the possible underlying mechanisms by which they induce ONJ. It is a known fact that ONJ is a debilitating condition, yet it is preventable if appropriate measures are instituted. Accordingly, we will highlight the latest recommendations put forth by medical societies so as to reduce the occurrence of ONJ in patients receiving those drugs.

Table 2 Staging and treatment strategies. Medication related osteonecrosis of jaw (MRONJ) staging

Recommended treatment approach

Stage 0

Pain medication and/or antibiotics

Stage 1 Stage 2

Stage 3

No clinical evidence of ONJ due to nonspecific symptoms, radiographic changes or clinical findings Presence of exposed and necrotic bone in patients with no symptoms or evidence of infection Presence of exposed and necrotic bone accompanied by pain, erythema and/or purulent drainage

Presence of exposed and necrotic bone

Antibacterial mouth wash Clinical follow up on a quarterly basis Antibacterial mouth wash, oral antibiotics and pain medications Debridement to relieve soft tissue irritation and infection control Antibacterial mouth wash, oral antibiotics and pain medications Surgical debridement for linger term palliation of infection and pain

Proposed mechanisms of BP induced ONJ Bisphosphonates are structurally related to inorganic pyrophosphate where the O atom that links the two phosphate moieties together in pyrophosphate is replaced by a C atom, thereby conferring stability and resistance to degradation by osteolytic enzymes

Table 3 Drugs associated with ONJ. Drug

*

Mode of action *

Half life

Dose

Route

Approved indication

At least 10 years

5–10 mg daily 35–70 mg weekly

Oral

Treatment and prevention of osteoporosis

Alendronate

Inhibition of FPS

Risendronate

Inhibition of FPS*

480–561 h

5 mg daily 35 mg weekly 150 mg monthly

Oral

Treatment and prevention of osteoporosis

Ibandronate

Inhibition of FPS*

IV: 5–25 h Oral: 37–157 h

150 mg monthly 3 mg every 3 months

Oral IV

Treatment and prevention of osteoporosis

Pamidronate

Inhibition of FPS*

21–35 h

60–90 mg every 3–4 weeks

IV

Prevention of SRE Hypercalcemia of malignancy Paget disease

Zolendronate

Inhibition of PFS*

167 h

5 mg yearly 4 mg every 3–4 weeks

IV

Osteoporosis Prevention of SRE Hypercalcemia of malignancy Paget disease

Denosumab

Inhibition of bone remodeling by blocking RANKL

25–28 days

60 mg every 6 months 120 mg every 3–4 weeks

SC

Osteoporosis Prevention of SRE Hypercalcemia of malignancy

Bevacizumab

Inhibition of angiogenesis by blocking action of VEGF

11–50 days

5–10 mg every 2 weeks 15 mg every 3 weeks

IV

Metastatic colorectal carcinoma Glioblastoma Metastatic NSCLC Metastatic renal carcinoma

Sunitinib

Inhibition of tyrosine kinase of VEGFR, PDGFR, FLT3, c-kit

40–60 h

50 mg daily for 4 weeks of a 6 week cycle

Oral

GIST Metastatic renal cell carcinoma Neuroendocrine tumors

Sorafenib

Inhibition of tyrosine kinase of VEGFR, PDGFR, FLT3, c-kit, BRAF

25–48 h

400 mg twice daily

Oral

Metastatic hepatic carcinoma Metastatic renal cell carcinoma

Everolimus

Inhibition of mTOR

30 h

0.75–1 mg twice daily 10 mg daily

Oral

Kidney and liver transplant Hormone receptor positive breast cancer Metastatic renal cell carcinoma

Temsirolimus

Inhibition of mTOR

17 h

25 mg weekly

IV

Metastatic renal cell carcinoma

Cabozantinib

Inhibition of tyrosine kinase of VEGFR, MET, RET

55 h

140 mg daily

Oral

Metastatic medullary thyroid cancer

FPS: farnesyl pyrophosphate synthase.

I.S. Hamadeh et al. / Cancer Treatment Reviews 41 (2015) 455–464 Table 4 Classification of bisphosphonates based on chemical structure. Non-nitrogen containing bisphosphonates (non N-BPs) Alkyl-amino bisphosphonates (alkyl-amino BPs) Heterocyclic nitrogen containing bisphosphonates (N-BPs)

Etidronate, clodronate Pamidronate, alendronate, ibandronate Risendronate, zoledronate

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one of the essential modulators of this process [11–13]. In addition to their ‘‘anti-osteoclastic effects, bisphosphonates can also suppress angiogenesis through a direct inhibitory effect on the endothelial cells. Hence, it is most likely that BP induced ONJ is a consequence of their anti-osteoclastic and anti-angiogenic effects. Review of clinical uses of bisphosphonates

Table 5 Relative potencies of bisphosphonates. Bisphosphonate

Relative potency

Etidronate Clodronate Pamidronate Alendronate Ibandronate Risendronate Zoledronate

1 10 100 100–1000 1000–10,000 1000–10,000 >10,000

secreted by the osteoclasts during bone resorption. Like pyrophosphate, bisphosphonates bind avidly to hydroxyapatite [4], the major inorganic constituent of the bone matrix, and this intrinsic property manifests itself in the rapid clearance of bisphosphonates from plasma (approximately 2 h) due to preferential deposition of 60% of the absorbed oral dose into the bone [5]. From a structural standpoint, bisphosphonates can be broadly classified into two main categories (Table 4): non-nitrogen containing bisphosphonates and nitrogen containing bisphosphonates where the latter is further broken down into the alkylamino bisphosphonates and the heterocyclic nitrogen containing bisphosphonates. The differences in chemical structure dictate the differences in potencies among members of this class of pharmacological agents [5] as illustrated in Table 5. Alkylamino bisphosphonates (pamidronate and alendronate) are 100 times more potent that non-nitrogen containing bisphosphonates such as etidronate which has currently fallen out of favor due to the presence of more effective bisphosphonates. Ibandronate, an alkylamino bisphosphonate that contains a tertiary nitrogen atom exhibits a greater potency for bone resorption inhibition relative to that of alendronate or pamidronate. The newest generation of bisphosphonates such as zoledronate which bears a heterocyclic nitrogen atom, has the greatest potency of all members belonging to this therapeutic drug class. During the bone resorption process, the acidic environment created in the bone releases the bisphosphonate from its hydroxyapatite bound form and the former is further taken up into the neighboring osteoclasts. Inside the osteoclasts, non-nitrogen containing bisphosphonates are converted to adenosine triphosphate (ATP) analogs by virtue of their structural resemblance to pyrophosphate. Accumulation of such metabolites inside the osteoclast eventually triggers cell apoptosis which eventually impairs bone resorption [6,7]. Nitrogen containing bisphosphonates inhibit bone resorption via a distinctive mechanism [8]. Studies have shown that the cellular target of all nitrogen containing bisphosphonates is farnesyl pyrophosphate synthase, the inhibition of which ultimately halts the production of prenylated forms of guanosine triphosphate binding proteins also referred to as ‘‘small GTPases’’ (Ras, Rho, Rac, etc. . .) which are involved in the regulation of a variety of cellular processes including bone resorption [9,10]. As a consequence of disrupting the downstream signaling pathways of the small GTPases, osteoclast mediated bone resorption is suppressed via this process. Although the intricacies of bone remodeling are beyond the scope of this paper, it is important to point out that vascular endothelial growth factor (VEGF) is

There are several bisphosphonates on the US market available for the treatment of a variety of ailments. In this section of the paper, we will discuss the clinical efficacy and the main indications for the use of these agents. Bisphosphonates have a well-established therapeutic role for the treatment and prevention of osteoporosis. Findings from randomized clinical studies [14–18] designed to evaluate the clinical efficacy of bisphosphonates in patients with osteoporosis demonstrated that their use resulted in about a 40–50% reduction in the risk of spine fractures and a 25% reduction in the risk of hip fractures accompanied by about a 5–8% increase in bone mass density (BMD). Moreover, clinical practice guidelines advocate treatment with bisphosphonates for the prevention of osteoporosis in patients receiving long term glucocorticoids as well as the prevention of skeletal related events (SREs, spinal cord compression, pathologic fractures, and radiation therapy) among patients with multiple myeloma or other solid tumors (breast, lung, prostate, etc. . .) that has metastasized to the bones. For the prevention of SREs, studies revealed that the administration of pamidronate or zoledronate every 28 days conferred a 20–50% reduction in the rates of SRE and most importantly a 6-month prolongation in the time to the first SRE in comparison with placebo [19,20–24]. Although the zoledronate label does not bear an approved indication for breast cancer treatment in combination with adjuvant chemotherapy, there is some evidence in the literature to support its use in postmenopausal women (5 years and above) with early stage breast cancer (disease free survival rate: 78.2% vs. 71.0%, p = 0 .02, and overall survival rates: 84.6% vs. 78.7%, p = 0.004) [25]. Despite the widespread use of bisphosphonates in clinical practice, ONJ remains one of the most feared complications associated with their use. In the subsequent sections of this paper, we will provide an overview of some of the most validated risk factors that when present, predispose patients to develop ONJ. Risk factors for BP related ONJ The reported cases linking bisphosphonate use to the incidence of ONJ were described initially with IV bisphosphonates (zoledronate and pamidronate) which are currently the mainstay of therapy for the prevention of SREs. The fact that the IV route results in complete delivery of the bisphosphonate into the blood stream (less than 1% of the dose is absorbed following oral administration) may partly explain the higher prevalence of ONJ with IV bisphosphonate use. Observational studies investigating the relationship between BP use and ONJ incidence [25–29] noted that the majority of the ONJ cases (88–95%) occurred in patients who received IV bisphosphonates (zoledronate or pamidronate) for multiple myeloma (44–52.1%), breast cancer (38.8–42%) or other solid malignancies while the remaining (5–12%) were among patients treated with oral bisphosphonates (mainly alendronate) for osteoporosis. Moreover, 75–86% of the cases had an inciting event (tooth extraction or dental surgery) that elicited the development of ONJ whereas the remaining 14–25% occurred spontaneously. Besides the route of administration, there are other risk factors that need to be taken into account when assessing the overall risk of bisphosphonate associated ONJ such as the cumulative dose of a

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bisphosphonate. To illustrate this further, the typical dose of zoledronate for the treatment of osteoporosis is 5 mg every 12 months. On the other hand, the cumulative dose of zoledronate for the prevention of SREs is 48 mg over a 12 months period (4 mg every 4 weeks). Hence, exposure to zoledronate is at least 10 times greater in cancer or multiple myeloma patients as opposed to osteoporosis patients. The same concept applies to denosumab which is discussed in subsequent sections (exposure to denosumab in cancer patients is 12 times greater). The duration of exposure has also been implicated as one of the risk factors for ONJ pathogenesis where the absolute risk is less than 1% during the first 12 months of treatment with IV bisphosphonates, and escalates gradually with prolonged exposure [29]. It should be emphasized that the time period to first occurrence of ONJ varies from one bisphosphonate to the other, primarily due to differences in potencies. Hence, the time to first occurrence of ONJ is expected be the shortest with zoledronate owing to its greater potency. Durie and colleagues [30] noted that the mean exposure time to IV zoledronate until the occurrence of ONJ is about 36 months compared to 6 years in patients receiving IV pamidronate. Other studies also reported similar findings [29,31], thereby substantiating the relevance of bisphosphonate potency as one of the contributing risk factors for the development of ONJ. Of note, current guidelines do not provide a clear cut recommendation in regard to the treatment duration of bisphosphonates. Nevertheless, most health care provider feel compelled to continue treatment until the patient’s condition declines drastically. Because multiple myeloma and solid tumor survival rates have improved tremendously over time, it is most likely that patients with these conditions will receive IV bisphosphonates for a minimum of 2 years which places them at a greater risk for developing bisphosphonate induced ONJ with prolonged exposure.

reported cases of ONJ with oral bisphosphonates when used for the treatment of osteoporosis, the risk appears to be minimal i.e. at least 10 times less than that observed with IV bisphosphonates even among chronic users (greater than 4 years), approximating 0.2% [32]. Given this low rate of ONJ with oral bisphosphonates, most physicians are reluctant to discontinue the drugs in osteoporosis patients who require dental manipulation or surgical procedure. RANKL inhibitor (denosumab) Proposed mechanism of ONJ with denosumab Denosumab is a fully humanized monoclonal antibody directed against RANKL (receptor activator of NFjB ligand), a member of the TNF superfamily which plays a key or critical role in regulating bone resorption. RANKL is secreted by activated osteoblasts in response to circulating cytokines (interleukins) and hormones (glucocorticoids). Upon binding to its surface receptors, RANKL triggers an intracellular signaling cascade that ultimately results in osteoclast maturation and proliferation. Denosumab binds with high affinity and specificity to RANKL, thereby blocking the ability of the latter to bind to the RANK receptors. Via this distinctive mechanism, denosumab exerts potent antiresorptive effects. Since ONJ is the end product of disrupted bone remodeling, it is reasonable to draw the conclusion that ONJ may also occur with denosumab therapy. Unlike bisphosphonates which have the tendency to accumulate and persist in the bone for several years after discontinuation of therapy, denosumab can linger in the body for a finite period of time by virtue of its low affinity to hydroxyapatite. With a half-life of 25–32 days, the effects of denosumab are expected to be short-lived and thus dissipate within 6 months of therapy cessation.

Incidence of BP related ONJ Review of clinical uses of denosumab Based on data from several studies, the incidence rates of bisphosphonate related ONJ ranged from 0.85% to 18.6% (Table 6). Several factors might have accounted for this wide variability in the rates of bisphosphonate induced ONJ such as differences in study design (prospective vs. retrospective), bisphosphonate exposure period, and most importantly the heterogeneity that existed among the patients enrolled in those studies as it pertains to the presence of well-established risk factors for ONJ (dental surgical procedures, periodontal disease, diabetes, smoking, other comorbid conditions, etc. . .). Therefore, extrapolating those findings to a real world setting so as to determine or predict the true risk of ONJ in a BP recipient could be quite challenging. Yet, all these studies demonstrated that multiple myeloma patients are more likely to develop BP induced ONJ than patients with solid tumors such as breast cancer or prostate cancer. It should be kept in mind that most if not all multiple myeloma patients are treated with steroids (dexamethasone or prednisone) in addition to lenalidomide or thalidomide as part of their induction regimens. Both thalidomide and its congener, lenalidomide disrupt angiogenesis or formation of new blood vessels although the exact mechanism is yet to be discovered. As discussed previously and in the next sections, VEGF plays an essential role in the bone remodeling process. Accordingly, inhibition of this pathway by drugs such as lenalidomide and thalidomide may explain why multiple myeloma patients may be more susceptible to developing bisphosphonate related ONJ than other patient populations. One important question to address relates to the prevalence of ONJ among patients treated with oral or IV bisphosphonates for osteoporosis where these agents are administered not only at lower doses but also less frequently. Despite the presence of

Over the past two decades, IV bisphosphonates (mainly IV zoledronate and pamidronate) have been an integral component of the armamentarium for the prevention of cancer therapy induced bone loss (CTIBL). Despite bisphosphonate therapy, SREs cannot be fully averted; about 50% of the patients treated with either IV pamidronate or zoledronate may still experience a SRE during the course of their disease [33]. Hence, additional treatment options are required for patients who do not respond adequately or are intolerant to bisphosphonates. For these patients, denosumab offers an effective and well tolerated alternative. Clinical trials randomizing patients with metastatic bone disease from either breast cancer or castration resistant prostate cancer to receive either subcutaneous denosumab 120 mg or IV zoledronate every 4 weeks revealed that denosumab therapy fared better that IV zoledronate in terms of prolonging the time to the first SRE [34,35] defined in most studies as pathologic fracture, radiation or surgery to the bone, or spinal cord compression. Furthermore, Lipton and colleagues [36], conducted a meta-analysis of three randomized clinical studies that included a total of 5723 patients recruited from 705 sites (2862 allocated to denosumab and 2861 to IV zoledronate where baseline and disease characteristics were well-balanced between the two treatment arms). According to this meta-analysis, treatment with denosumab was more effective than IV zoledronate in terms of reducing the risk of the first SRE which translated into a 17% reduction in the rates of SRE among denosumab users vs. zoledronate users (HR: 0.83, 95% CI: 0.76–0.9, p < 0.001) [36]. Furthermore, the time to the first on study SRE and the time to the first hypercalcemia of malignancy were simultaneously delayed by denosumab with a difference of 8.21 months (19.45 months, 95% CI:

459

I.S. Hamadeh et al. / Cancer Treatment Reviews 41 (2015) 455–464 Table 6 Studies evaluating incidence of osteonecrosis of jaw with bisphosphonates. Study

# of patients

Bisphosphonates (IV): Vahtsevanos et al. 1621 [63]

Bamias et al. [29]

252

Dimopoulos et al. [64]

202

Durie et al. [30]

1203

Age (years)

Disease (%)

Type of IV bisphosphonate

Exposure

Incidence of ONJ

Mean (SD): 63.6 (9.8)

MM: 33.3%

Zoledronate

Overall: 5%

BC: 64.2% PC: 2.5%

Pamidronate Ibandronate Two agents

Mean # of doses: MM: 19.2 (12.6) BC: 17.4 (12.3) PC: 14.1 (9.4)

MM: 44%

Zoledronte

Overall: 6.7%

BC: 27.7% PC: 18.2% Other: 9.95

Pamidronate Ibandronate Two agents

Median time of exposure (range) MM: 28.4 months (4.5-86) BC: 17.9 months (4–77.8) PC: 14.4 months (4–66.5) Other: 10.7 months (4.4–47.3)

MM: 100%

Zoledronate Pamidronate Ibandronate Two agents

Median time of exposure (range): 29 months (4.5–123)

Overall: 7.4%

MM: 75.1%

Zoledronate

Not reported

BC: 24.9%

Pamidronate

Overall: 12.6% MM: 12.8% BC: 12%

Median (range): 61 (43–72)

Median (range): 64 (26–73)

MM: 8.5% BC: 3.1% PC: 4.9%

MM: 9.9% BC: 2.9% PC: 6.5% Other: 4%

Scagliotti et al. [65]

395

Median (range): 60 (54–68)

NSCLC:100%

Zoledronate

Not reported

Overall: 0.8%

Walter et al. [66]

43

Mean (SD): 70.2 (5.8)

PC: 100%

Zoledronate

# of infusions: at least 14

Overall: 18.6%

Stumpe et al. [67]

638

Median (range): 67 (32–98)

BC: 37.7%

Zoledronate

Median # of months (range): 17 (10–46)

MM: 20.1% PC: 12.4% LC: 12.1% Other: 17.7%

Pamidronate Both agents

Overall: 0.94% MM: 2.3% PC: 1.3% BC: 0.4%

MM: 73%

Zoledronate

Median time of exposure (range): 27 months (6–101)

BC: 13% Other: 14%

Pamidronate Both agents

Overall: 27.5% MM: 17.2% BC: 50% PC: 33.3%

Boonyapakorn et al. [68]

80

Median (range): 63 (28–76)

Wang et al. [69]

442

Not reported

MM:66.1% BC: 18.3% PC: 15.6%

Zoledronate Pamidronate Both agents

Not reported

Overall: 3.3% MM: 3.8% BC: 2.5% PC: 2.9%

Denosumab Scagliotti et al. [65]

406

Median (range): 60 (54–68)

NSCLC

Denosumab

Not reported

Overall: 0.8%

Henry et al. [70]

886

Median (range): 60 (18–89)

MM: 10% NSCLC: 39% Others (excluding BC and PC): 51%

Denosumab

Not reported

Overall: 1.1%

Stopeck et al. [34]

1026

Median (range): 57 (49–65)

BC: 1005

Denosumab

Not reported

Overall: 2%

BC: breast cancer, MM: multiple myeloma, PC: prostate cancer, LC: lung cancer, NSCLC: non small cell lung cancer.

18.5–21.4 for zoledronate vs. 27.6 months, 95% CI: 24.2-not estimable for denosumab) and 7.2 months (HR: 0.83, 95% CI: 0.76–0.9.0, p < 0.001), respectively. With the advent of denosumab, the landscape of SRE management has changed significantly. Although clinical practice guidelines societies do not favor one particular agent over the other, denosumab is listed as one of the treatment options for the prevention of SRE in patients with solid tumors who have evidence of bone metastases [37,38]. Denosumab is also indicated for the treatment of osteoporosis in postmenopausal women at high risk of fractures, as well as bone loss in women receiving aromatase inhibitor therapy for breast cancer and men receiving androgen depriving therapy (ADT) for prostate cancer. Findings from randomized clinical studies indicated that continued treatment with denosumab for 36 months reduced vertebral, non-vertebral and hip fracture risks by 68%,

20% and 40%, respectively [39–42]. Of note, a different brand of denosumab is used (ProliaÒ) for the treatment of osteoporosis mainly because of the distinct dosing schedule in this setting (60 mg every 6 months as opposed to 120 mg every 4 weeks in the setting of SREs).

Incidence of denosumab related ONJ Due to the superior efficacy of denosumab over zoledronate in the setting of bone metastases which can be traced to greater inhibition of bone resorption, it is only logical to infer that the rate of ONJ is higher with denosumab in comparison with zoledronate. Based on results from clinical trials comparing head to head the efficacy of denosumab with that of zoledronate for the prevention

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of the first SREs (Table 6), the rates of ONJ were not statistically significantly different between the two treatment arms i.e. the incidence of denosumab induced ONJ was comparable to that of bisphosphonates, ranging from 1% to 2% [34,35]. The results of the meta-analyses by Saad et al. further validate these findings [43]. ONJ occurred in 1.8% of patients treated with denosumab (52/2734) and 1.3% among those treated with zoledronate (37/ 2836); the difference in ONJ incidence rate was not statistically significant (p = 0.13). Furthermore, the median exposure time until ONJ development was 14 months (4–30 months) for both drugs and almost two thirds of the cases occurred following tooth extraction. Interestingly, the meta-analysis performed by Qi WX [44], the objective of which was to evaluate the risk of ONJ with antiresorptive agents revealed contradictory results. The meta-analysis included 8963 patients from 7 randomized clinical studies. The authors noted that the overall rates of ONJ were significantly higher with denosumab as opposed to bisphosphonates (RR: 1.61, 95% CI: 1.05–2.48, p = 0.029), and this was mostly driven by the higher rates of ONJ observed among prostate cancer patients receiving denosumab (RR: 3.358, 95% CI: 1.573–7.166, p = 0.002). In the osteoporosis setting, not a single case of ONJ was detected in any of the randomized clinical studies seeking to evaluate efficacy of denosumab [39,40,45]. After performing a search in PubMed, we were able to identify 8 case reports [46–52] of denosumab related ONJ, of which 4 occurred 2–4 months after tooth extraction in patients treated with denosumab for osteoporosis at the FDA approved dose (60 mg every 6 months). Due to the lack of solid evidence from clinical studies, the prevalence of ONJ among patients treated with denosumab for osteoporosis is difficult to assess or estimate. The aforementioned published case reports serve as the only proof of its existence. Therefore, it is pivotal that health care providers caring for patients with osteoporosis are cognizant of this potential risk. Anti-vascular endothelial growth factor therapies Several studies have shown that VEGF plays an essential or critical role in bone repair. Consequently, inhibition of the physiological effects of VEGF through use of VEGF antagonists which are also referred to as ‘‘anti-VEGF agents’’ could theoretically predispose patients to ONJ. From a mechanistic stand point, anti-VEGF therapies are broadly classified into categories: monoclonal antibodies that bind to VEGF and thereby neutralize its biological activity, and small molecule tyrosine kinase inhibitors (TKIs) that block the VEGF receptor and its downstream signaling pathways. In this section, we will provide an overview of the published literature on ONJ associated with the use of anti-VEGF agents. Clinical uses for bevacizumab Bevacizumab is a recombinant humanized immunoglobulin-G monoclonal antibody that specifically targets VEGF-A, an isoform of VEGF that promotes angiogenesis via activation of VEGFR type 1 and 2. After binding to VEGF-A, bevacizumab prevents the former from interacting with its receptors, and thereby inhibits angiogenesis or formation of new blood vessels. Bevacizumab is FDA-approved for variety of indications: metastatic colorectal cancer (in combination with a fluorouracil based regimen), glioblastoma (as monotherapy or in combination with irinotecan), metastatic non-small cell lung cancer (NSCLC) of the nonsquamous cell histopathological subtype (in combination with carboplatin and paclitaxel), and metastatic renal cell carcinoma (in combination with interferon). Furthermore, it is used off label for the treatment of triple negative metastatic breast cancer, ovarian cancer, and age related macular degeneration. Hence, it is not

surprising to find reported cases of ONJ associated with bevacizumab use.

Incidence of ONJ with bevacizumab The first case report associating bevacizumab with the incidence of ONJ was published by Estilo et al. back in 2008 [53]. In this case report, a 51 year old female with metastatic breast cancer treated with capecitabine (1500 mg in the morning and 1000 mg in the evening 2 weeks on and 1 week off) along with bevacizumab 15 mg/kg every 3 weeks, presented with bone protrusion in the lower jaw (mandible) 6 weeks after the administration of the 8th bevacizumab dose. Interestingly, the patient did not receive any bisphosphonate therapy for her metastatic disease and also denied any recent history of dental extraction. Cessation of both bevacizumab and capecitabine for a few weeks resulted in complete resolution of the exposed bone. To determine whether the use of bevacizumab is associated with an increased risk for ONJ, Guarneri et al. [54] analyzed the data from a single open label safety study (ATHENA), and two randomized controlled clinical studies (AVADO and RIBBON-1) set out to determine whether addition of bevacizumab improves clinical outcomes in patients with metastatic breast cancer. A total of 3560 patients were included in the final analysis, of whom 658 (18.4%) received IV bisphosphonates for the prevention of SREs. The authors noted an overall ONJ rate of about 0.4% (14/3560). Risk stratification based on bisphosphonate use revealed a 30-fold increase in the incidence of ONJ in patients who received bevacizumab with concomitant bisphosphonate therapy (1.8%, 12/658 vs. 0.06%, 2/2902 with bevacizumab alone). McArthur et al. from Memorial Sloan-Kettering Cancer Center (MSKCC) conducted a similar analysis which included 8681 patients. Of those patients, 75.6% (6561 patients), 19.7% (1711 patients), and 4.7% (409 patients) received IV bisphosphonates (pamidronate or zoledronate), bevacizumab and a combination of IV bisphosphonates and bevacizumab, respectively. The results from this analysis were concordant with what Guarneri et al. reported signifying a lower risk for ONJ among bevacizumab recipients (0.1%, 2/1711) compared with 1.1% (72/6561) in patients treated with an IV bisphosphonate and 2% (8/409) in those who received a combination of a bisphosphonate and bevacizumab. Furthermore, the retrospective study by Christodoulou et al. [56] also showed that the incidence of ONJ among bevacizumab recipients was lower (1.1%, 1/91) compared with those who received bevacizumab on top of bisphosphonates, mainly zoledronate and ibandronate (16%), and this difference was statistically significant (p = 0.008). Nonetheless, the rate of ONJ among bevacizumab recipients was at least 10-fold greater than what was reported in the studies by Guarneri et al. and McArthur et al. The high rates of ONJ observed in the study by Christodoulou and colleagues could be attributed to the retrospective nature of the study where the presence of other risk factors might have prompted the development of ONJ. Because the recognition of ONJ as a serious side effect of bisphosphonate therapy came about following the publication of several case reports associating this class of drugs with the occurrence of ONJ, we opted to search PUBMED for cases of ONJ related to bevacizumab using the search terms ‘‘bevacizumab’’ and ‘‘ONJ’’ or ‘‘avascular necrosis of the jaw’’. Accordingly, our search terms yielded 11 case reports (including the case report by Estilo), of which 4 implicated bevacizumab therapy alone (i.e. without the use of a BP) (Table 7). Only 2 case reports are not summarized in Table 7 because they were published as abstracts and we were not able to retrieve the full text. It is important to point out that in one case report, bevacizumab was administered intravitreally (into the vitreous body of the eye). Hence, the occurrence of ONJ

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I.S. Hamadeh et al. / Cancer Treatment Reviews 41 (2015) 455–464 Table 7 Case reports of ONJ associated with the use of bevacizumab and sunitinib. Reference or study

Age (years)

Gender

Indication

Treatment

Site of ONJ

Other risk factors

61

Male

Smoking and temsirolimus

Male

Bevacizumab IV 10 mg/kg every 2 weeks & temsirolimus 25 mg IV weekly mFOLFOX6+ bevacizumab

Left mandible

67

Magremanne et al. [73] Katsensos et al. [74]

49

Male

Bevacizumab

Male

Left posterior mandible Right posterior mandible

Corticosteroids

57

Metastatic renal cell carcinoma Metastatic sigmoid colon cancer Glioblastoma multiforme Metastatic NSCLC

Disel et al. [75]

51

Male

None

Hopp et al. [76]

58

Male

Posterior mandible Left mandible

Greuter et al. [77] Estilo et al. [53]

63

Female

Left maxilla

Tooth extraction

51

Female

Posterior mandible

None

Estilo et al. [53]

33

Female

Glioblastoma multiforme

Right mandible

None

65

Male

renal

off and 2 weeks

Right maxilla

62

Male

on and 2 weeks

Left mandible

IV zoledronate for metastatic bone disease IV zoledronate 4 mg every month

55

N/A

on and 2 weeks

Mandible

IV ibandronate 6 mg every month

56

N/A

Metastatic carcinoma Metastatic carcinoma Metastatic carcinoma Metastatic carcinoma

on and 2 weeks

Right (anterior) mandible

62

N/A

renal cell

63

Male

59

Male

58

Female

59

Male

64

Female

Metastatic carcinoma Metastatic carcinoma Metastatic carcinoma Metastatic carcinoma Metastatic carcinoma Metastatic carcinoma

Tooth extraction (right molar) IV zoledronate 4 mg every month started 1 month Smoking Tooth extraction IV zoledronate 4 mg every month IV pamidronate* Tooth extraction

Bevacizumab: Santos-Silva et al. [71] Sato et al. [72]

Sunitinib: Agrillo et al. [78] Agrillo et al. [78] Hoefert et al. [79] Hoefert et al. [79] Hoefert et al. [79] Balmor et al. [80] Kock et al. [81] Fleissig et al. [82] Brunello et al. [83] Galitis et al. [84]

Metastatic sigmoid colon Retinal vascular thrombosis Metastatic breast cancer Metastatic breast cancer

renal cell renal cell renal cell

Cistplatin IV 75 mg/m2 + paclitaxel IV 75 mg/m2 + bevacizumab 15 mg/kg every 3 weeks FOLFOX+ bevacizumab 5 mg/kg every 2 weeks Intravitreal bevacizumab 2.5 mg every month Liposomal doxorubicin + bevacizumab* Capecitabine 1000 mg twice daily (2 weeks on and 1 week off) + bevacizumab 15 mg/kg every 3 weeks Radiation (not including oral cavity and jaw) + temozolamide + bevacizumab 10 mg/kg every 2 weeks Sunitinib 50 mg 4 weeks off Sunitinib 50 mg 4 weeks off + temsirolimus* Sunitinib 50 mg 4 weeks off Sunitinib 50 mg 4 weeks off

renal cell

Sunitinib 50 mg 4 weeks on and 2 weeks off Sunitinib*

renal cell

Sunitinib 37.5 mg daily

renal cell

Sunitinib 50 mg 4 weeks on and 2 weeks off Sunitinib 50 mg 4 weeks on and 2 weeks off Sunitinib 50 mg 4 weeks on and 2 weeks off

renal cell renal cell

Left mandible Maxilla and palate Left posterior mandible Right mandible Left hemi mandible Mandible

Denture use + IV zoledronic acid 4 mg every month

None

Tooth (first molar) extraction Tooth (right lower third molar) extraction Previous treatment with IV zoledronate Denture use

NSCLC: non small cell lung cancer. * Dose not reported.

only suggests that the drug was able to cross the retinal blood barrier and reach the systemic circulation. Based on the available evidence, it seems plausible that bevacizumab use confers a relatively low risk for ONJ development. However, this risk becomes amplified if bevacizumab is added to a background of bisphosphonate therapy in which case the ONJ risk becomes comparable to if not greater than that observed with bisphosphonates. Incidence of ONJ with TKI Unlike bevacizumab, TKIs are orally administered small molecules that inhibit tyrosine kinase activity of several receptors such as VEGFR (1–3), PDGFR, and c-Kit, as well as others. Because TKIs antagonize the effects of VEGF, it is highly possible that the risk of ONJ exists with these drugs. Incidence of ONJ with Sunitinib Sunitinib is considered one of the first line agents for the treatment of metastatic renal carcinoma, and it is used as second-line

therapy for the treatment of gastrointestinal stromal tumors (GIST) after failure of imatinib therapy. Due to its widespread use in the oncology setting in particular in renal carcinoma, several case reports linking sunitinib treatment to ONJ occurrence started surfacing after its approval (refer to same table as bevacizumab, Table 7). Of note, most renal carcinoma patients present with late stages of the disease i.e. with metastatic bone disease for which IV bisphosphonates are initiated as a preventative measure or approach against SREs which poses a great challenge in terms of not only establishing a causal relationship between ONJ and sunitinib, but also estimating the risk of sunitinib related ONJ. Hansen et al. [55] conducted a retrospective chart review to assess the safety of targeted therapy namely sunitinib in patients with metastatic renal carcinoma. The excessively high incidence of ONJ noted in this study (29%) could only be ascribed to the co-administration of zoledronate to all sunitinib treated patients. Randomized clinical trials of sunitinib for the treatment of renal carcinoma or gastrointestinal stromal tumor (GIST) did not report cases of ONJ among sunitinib recipients. Because sunitinib interferes with the VEGF signaling pathway, it is most likely that the risk of sunitinib related ONJ approximates that of bevacizumab (0.2–0.4%). In PUBMED,

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there are 4 published ONJ cases (Table 7) describing sunitinib as the culprit given the fact that none of the patients who developed ONJ had a previous history of or exposure to bisphosphonate treatment, thereby raising the possibility that sunitinib, due to its antiVEGF activity, may also cause ONJ. Incidence of ONJ with other TKIs Other TKIs available for use in clinical practice which are similar to sunitinib from a mechanistic stand point include: axitinib, pazopanib and cabozantinib. Besides VEGFR receptor inhibition, these drugs block the biological activities of other receptor tyrosine kinases. To our knowledge, case reports describing ONJ with the use of sorafenib, axitinib and pazopanib are currently lacking. However, we were able to come across a single case report [56] about a 51 year old female patient with medullary thyroid cancer treated with cabozantinib (dose not specified). Two months after tooth extraction, the patient presented with ONJ, presumably caused by cabozantinib since the patient had no previous history of BP treatment. In the phase III randomized clinical trial performed by Elisei et al. [57] which evaluated the efficacy of cabozantinib in patients with metastatic medullary thyroid cancer, 3 of the 219 (1.4%) patients allocated to the cabozantinib arm developed ONJ, of whom 1 patient had a grade-3 ONJ. In addition, about 51% of patients in the cabozantinib arm had bone involvement; however the authors did not state whether such patients were receiving an IV bisphosphonate. The low prevalence of medullary thyroid cancer alongside the current approval status of cabozantinib, currently restricted to metastatic medullary thyroid cancer, only suggest that there will be a paucity in the number of reported cases of cabozantinib induced ONJ. However, this is definitely subject to change if the drug is granted approval for treatment of other types of metastatic solid tumors. Incidence of ONJ with mTOR inhibitors Inhibitors of mammalian target of rapamycin (mTOR) such as everolimus, and temsirolimus are a relatively new class of therapies that are mainly used in the treatment of metastatic renal carcinoma. Everolimus is also approved for other indications such as: hormone positive breast cancer (in combination with exemestane), pancreatic neuroendocrine tumors, and prevention of solid organ rejection. Because mTOR signaling is regulated by the VEGF pathway, it is also reasonable or plausible to expect some reported cases of ONJ with the use of these agents. Currently, there are two published cases of ONJ with everolimus. In the case report by Giancola and colleagues [58], an association between everolimus and ONJ incidence is hard to infer in light of the fact that the 64 year old patient had been on zoledronate for the past 2 years for bone metastasis from renal cell carcinoma prior to the addition of everolimus at a daily dose of 10 mg. Although the patient presented with ONJ 6 months after the introduction of everolimus, it is most likely that zoledronate was the culprit. Yet, the possibility that the addition of everolimus exacerbated the condition should not be ruled out or precluded. In the second report by Kim and colleagues [59], everolimus might have been the trigger for ONJ since at least 6 years had elapsed since the last administered dose IV zoledronate making it highly unlikely that this adverse event might have been exacerbated by the concomitant use of a BP. Role of genetic factors Given the fact that ONJ occurs in only a small minority of patients receiving these drugs, some studies sought to investigate

the impact of certain genetic polymorphisms on the incidence of ONJ. Sarasquete et al. [60] conducted a genome wide association study (GWAS) where a total of about 300,000 SNPs were tested for association with ONJ. The study included 675 patients, of whom 24 (3.6%) had ONJ. After a median follow up of 64 months, the authors were able to identify 4 SNPs across the human genome that were significantly correlated with the incidence of ONJ. Furthermore, the 4 SNPs were mapped to the CYP2C8 gene located on chromosome 10. CYP2C8 enzyme is mainly expressed in the liver. Nevertheless, none of the currently available bisphosphonates undergoes metabolism by the hepatic enzymes which raises concerns over the validity of such a finding since it was not replicated in other studies. It should be kept in mind that CYP2C8 is involved in several biologic pathways that play a significant role in regulating vascular tone. As an example, CYP2C8 mediates the conversion of arachidonic acid (AA) to epoxyeicosatrienoic acid which is a potent vasodilator. This finding suggests that patients carrying polymorphisms in CYP2C8 gene maybe genetically predisposed to the incidence of ONJ when treated with bisphosphonates as a consequence of impaired blood flow. Katz et al. [61] conducted a study to determine whether polymorphisms in genes known to be involved in bone remodeling and turnover could predict the risk of developing of ONJ among multiple myeloma patients treated with IV pamidronate or zoledronate. Accordingly, only 10 known SNPs in the following 7 genes were genotyped and assessed for association with ONJ: CYP2C8, COL1A1, RANK, OPN, MMP2, OPG, and TNF. The authors noted that although there was a trend towards a higher risk of ONJ in patients harboring polymorphisms in one of the five genes: COL1A1, RANK, MMP2, OPG, and OPN, the risk was 11-folds higher in individuals who carried the five polymorphisms altogether. Findings from this study insinuate that the pathology of ONJ is complicated and is most likely brought about by inhibition of bone remodeling and bone turnover. Although previous studies have demonstrated that suppression of angiogenesis may contribute to the incidence of ONJ, the studies by Katz et al. and Sarasquete et al. did not specifically investigate the impact of polymorphisms in the VEGF gene on the risk of ONJ. As a consequence, further studies are needed to identify genetic markers that may predispose patients to ONJ.

Prevention of drug induced ONJ ONJ is considered a challenging dilemma for health care providers mainly due to our limited knowledge of its pathogenesis, and the lack of biomarkers that can be utilized as a screening tool in clinical practice to identify patients who will most likely develop it following the initiation of high risk drugs. We have witnessed a drastic decline in the incidence of ONJ over the past few years, and this is reflective of the increased awareness among health care providers of this condition. Furthermore, the availability of position papers that provide guidance on how to manage patients receiving drugs associated with ONJ, have unquestionably played a pivotal role in curtailing the incidence of this disease. Because most reported ONJ cases occurred after invasive dental procedures, current recommendations from medical societies advocate early screening and implementation of appropriate dental measures prior to initiation of pharmacotherapies that predispose patients to developing ONJ. Hence, early dental examination is key for ONJ prevention. It is worth noting that those recommendations emanated from evidence [62] demonstrating at least a 3-fold reduction in rates of ONJ among patients who were screened and received appropriate dental care prior to treatment with high risk drugs. Yet, such preventative measures can only minimize the risk of ONJ, but cannot totally abolish it, suggesting that the incidence of ONJ is multifactorial and there are other risk factors, aside from

I.S. Hamadeh et al. / Cancer Treatment Reviews 41 (2015) 455–464

invasive dental procedures that play a role in the pathogenesis of ONJ. An area of ongoing debate is what the appropriate management or course of action is for patients who are receiving high risk medications, and require dental extraction or an invasive dental procedure. Most guidelines propose the institution of drug holidays despite the lack of solid evidence to support this strategy. Accordingly, oral bisphosphonates should be discontinued for at least 2 months in high risk patients (defined as those who have been on oral bisphosphonates for more than 4 years, smokers, diabetics, or patients with treated with corticosteroids), and then resumed after complete bone healing. For patients requiring IV bisphosphonates for SREs, preventive dental care should be performed prior to treatment with these agents. Unlike IV bisphosphonates, the short half-life of denosumab can be exploited in such instances where its discontinuation for about 6 months (5 half-lives) if possible will most likely result in total clearance of denosumab and thereby portend a low risk for ONJ occurrence. The same principle can be applied to other drugs that do not accumulate in the bone (bevacizumab, sunitinib, etc. . .) if a dental surgical procedure is deemed necessary.

[9]

[10]

[11] [12] [13]

[14]

[15]

[16]

[17]

Conclusion After reviewing the literature on drug induced ONJ, it is obvious that there is a wide knowledge gap in our understanding of ONJ. Hence, we believe that intensive investigation is still needed to advance our perception of the disease pathology, discover biomarkers that can be utilized in clinical practice as screening tools to identify patients at risk of developing ONJ, and finally develop alternative dosing strategies to avert ONJ development among high risk individuals so as to improve patient safety and improve their quality of life. Conflict of interest

[18]

[19]

[20]

[21]

[22]

No conflicts to be disclosed. [23]

Acknowledgement [24]

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