Novartis Pharmaceuticals Corporation

59 Route 10

East Hanover, NJ 07936

**BACKGROUND INFORMATION**

**FOR**

**Oncologic Drugs Advisory Committee Meeting**

**March 4, 2005**

**Zometa^®^ (zoledronic acid) Injection**

**and**

**Aredia^®^ (pamidronate disodium) Injection**

**Submitted: February 1, 2005**

## Table of contents {#table-of-contents .TOC-Entry}

Table of contents [2](#table-of-contents)

List of tables [3](#list-of-tables)

1 Executive summary [5](#executive-summary)

2 Background on Zometa [6](#background-on-zometa)

3 Osteonecrosis (ON) -- background information
[8](#osteonecrosis-on-background-information)

3.1 Introduction [8](#introduction)

3.2 Risk factors for ON [9](#risk-factors-for-on)

3.2.1 Corticosteroids as a risk factor for ON
[9](#corticosteroids-as-a-risk-factor-for-on)

3.2.2 Coagulopathy as a risk factor for ON
[10](#coagulopathy-as-a-risk-factor-for-on)

3.3 ON in cancer patients [10](#on-in-cancer-patients)

3.4 Osteonecrosis of the jaw (ONJ) [12](#osteonecrosis-of-the-jaw-onj)

3.5 ONJ in cancer patients [14](#onj-in-cancer-patients)

3.6 Preclinical data on bisphosphonates and osteonecrosis
[15](#preclinical-data-on-bisphosphonates-and-osteonecrosis)

4 Reported cases of osteonecrosis of the jaw
[16](#reported-cases-of-osteonecrosis-of-the-jaw)

4.1 Cases of ONJ reported in the literature
[16](#cases-of-onj-reported-in-the-literature)

4.2 Cases of ONJ reported to Novartis
[18](#cases-of-onj-reported-to-novartis)

4.2.1 Completed studies [21](#completed-studies)

4.2.2 Ongoing studies [23](#ongoing-studies)

4.3 Preliminary findings from retrospective chart review at MD Anderson
Cancer Center
[24](#preliminary-findings-from-retrospective-chart-review-at-md-anderson-cancer-center)

5 Regulatory background [26](#regulatory-background)

6 Novartis initiatives concerning reports of ONJ
[27](#novartis-initiatives-concerning-reports-of-onj)

6.1 Initiation of reporter communications
[27](#initiation-of-reporter-communications)

6.2 Review and changes of prescribing information
[28](#review-and-changes-of-prescribing-information)

6.3 Advisory boards and patient management
[28](#advisory-boards-and-patient-management)

6.4 Change of informed consent [29](#change-of-informed-consent)

7 Novartis continued due diligence
[29](#novartis-continued-due-diligence)

8 Novartis assessment and recommendations
[31](#novartis-assessment-and-recommendations)

8.1 Overall assessment of ONJ [31](#overall-assessment-of-onj)

8.2 Benefit risk assessment [34](#benefit-risk-assessment)

8.3 Novartis recommendation [34](#novartis-recommendation)

8.3.1 Additional studies [34](#additional-studies)

8.3.2 Continue to promote awareness [35](#continue-to-promote-awareness)

9 References [35](#references)

## List of tables {#list-of-tables .TOC-Entry}

Table 2-1 Efficacy summary of Zometa in patients with prostate cancer
\[Study 0039\]
[8](#table-2-1-efficacy-summary-of-zometa-in-patients-with-prostate-cancer-study-0039)

Table 2-2 Efficacy summary of Zometa in patients with lung cancer and
other solid tumors \[Study 0011\]
[8](#table-2-2-efficacy-summary-of-zometa-in-patients-with-lung-cancer-and-other-solid-tumors-study-0011)

Table 3-1 Cases of osteonecrosis after chemotherapy for solid tumors
(from Winquist et al, 2001)
[10](#table-3-3-cases-of-osteonecrosis-after-chemotherapy-for-solid-tumors-from-winquist-et-al-2001)

Table 3-2 Selected studies of corticosteroid-induced osteonecrosis
\[adapted from (Assouline-Dayan et al, 2002)\]
[12](#table-3-4-selected-studies-of-corticosteroid-induced-osteonecrosis-adapted-from-assouline-dayan-et-al-2002)

Table 4-1 References 2004 [17](#table-4-5-references-2004)

Table 4-2 Reports of ONJ (including reportable cases from the
literature) associated with the use of Zometa/Aredia (as of December 7,
2004)
[18](#table-4-6-reports-of-onj-including-reportable-cases-from-the-literature-associated-with-the-use-of-zometaaredia-as-of-december-7-2004)

Table 4-3 Completed Zometa and Aredia studies included in the search for
terms related to ONJ using MedDRA terms
[20](#table-4-7-completed-zometa-and-aredia-studies-included-in-the-search-for-terms-related-to-onj-using-meddra-terms)

Table 4-4 Summary of the ONJ cases in randomized pivotal clinical trials
[22](#table-4-8-summary-of-the-onj-cases-in-randomized-pivotal-clinical-trials)

Table 4-5 ONJ/OMJ cases reported in pivotal bone metastases and
hypercalcemia trials: possible risk factors
[23](#table-4-9-onjomj-cases-reported-in-pivotal-bone-metastases-and-hypercalcemia-trials-possible-risk-factors)

Table 4-6 ONJ cases reported in ongoing Zometa bone metastases studies
[23](#table-4-10-onj-cases-reported-in-ongoing-zometa-bone-metastases-studies)

Table 4-7 Demographics of patients included in the review
[25](#table-4-11-demographics-of-patients-included-in-the-review)

Table 4-8 Brief overview of 18 ONJ cases from MD Anderson Cancer Center
[25](#table-4-12-brief-overview-of-18-onj-cases-from-md-anderson-cancer-center)

Table 8-1 Summary of ONJ for datasets
[32](#table-8-13-summary-of-onj-for-datasets)

**List of Appendices**

Appendix 1: Risk Factors/Conditions for Osteonecrosis

Appendix 2: Osteonecrosis in Cancer Patients

Appendix 3: Comprehensive Medical Safety Evaluation Osteonecrosis of the
Maxillofacial Area December 2004 Overview

Appendix 4: ONJ in Clinical Studies

Appendix 5: The University of Texas, M.D. Anderson Cancer Center, Study
Protocol -- Retrospective Chart Review to Collect information on the
Frequency of Osteonecrosis in Patients Treated with Intravenous
Bisphosphonate

Appendix 6: Summary of ONJ Cases from Retrospective Chart Review at MD
Anderson Cancer Center

Appendix 7: Package Insert Revisions, re: Osteonecrosis of the Jaw

Appendix 8: Patient Information Form (Bisphosphonates and ONJ)

Appendix 9: Dear Doctor Letter

Appendix 10: Advisory Board Attendees

Appendix 11: Expert Panel Recommendation for the Prevention, Diagnosis
and Treatment of Osteonecrosis of the Jaw

# Executive summary

Osteonecrosis of the jaw (ONJ) is a vaguely defined and poorly
understood clinical entity. The etiology and pathogenesis of ONJ are not
clear, but multiple risk factors are involved, including a diagnosis of
cancer, concomitant therapies (e.g. chemotherapy, radiotherapy,
corticosteroids), and co-morbid conditions (e.g. anemia, coagulopathies,
infection, pre-existing oral disease). The management of ONJ can be
challenging, though patients' discomfort can be reduced with appropriate
medical intervention.

ONJ in cancer patients treated with bisphosphonates was first reported
to Novartis in December 2002. Novartis took immediate action to collect
detailed information on the reported cases in an effort trying to
understand ONJ. Subsequently, Novartis took various steps to enhance the
awareness of ONJ among healthcare professionals and patients, including
revision of patient informed consent for clinical trials, dissemination
of a patient brochure on ONJ and distribution of a Dear Doctor letter
(Appendix 9). Novartis also revised the package inserts for both
Aredia^®^ and Zometa^®^ to provide information on post-marketing reports
of ONJ and guidance on the prevention and treatment of this condition.

Novartis has carefully reviewed and analyzed the available data on ONJ,
which are included in this submission. The background rate of ONJ in
cancer patients not treated with a bisphosphonate is unknown. In
addition, the number of ONJ cases in clinical trials is small. The
majority of information on this condition is derived from uncontrolled
case series. Therefore, a causal relationship between bisphosphonate
therapy and ONJ cannot be established.

In order to protect patients, there is a need to continue efforts to
understand this condition in cancer patients, including the
identification of risk factors for ONJ. In addition, clinical data may
be required for healthcare professionals to develop treatment plans for
patients at risk for ONJ, to optimize management of patients with ONJ
while on bisphosphonate therapy, and to guide physicians on how to
change treatment plans if patients encounter risk factors such as a need
for dental extraction during bisphosphonate treatment.

Zometa and Aredia provide significant benefit to patients with multiple
myeloma and bone metastases from solid tumors by reducing the risk of
serious skeletal complications. When assessing benefit/risk, it is
important to consider the critical difference between Zometa and Aredia
in that Zometa has a broader range of activity in tumors where Aredia is
inactive. Novartis is committed to further the safety of these patients
by continuing to investigate ONJ and educate patients and healthcare
professionals about this condition and its management. We hope the
meeting with the FDA and Advisory Committee Members will provide us with
additional insight and guidance for our future activities in
understanding ONJ in cancer patients.

# Background on Zometa

Zoledronic acid (Zometa^^) is a third generation nitrogen-containing
bisphosphonate developed to treat patients with multiple myeloma or
solid tumor and bone metastases, where skeletal complications frequently
occur due to bone lesions (Coleman 1997). Bone metastases are either
osteolytic (osteoclastic) or osteosclerotic (osteoblastic). Osteolytic
metastases are caused by tumor associated cytokine activation of
osteoclasts leading to increased bone resorption, bone lesion, and
eventually bone complications (Mundy 2001; Mundy 2002). The pathogenesis
underlying osteosclerotic metastases is less well defined but tumor
related endothelin secretion has been implicated as an important
pathogenetic factor (Guise 2004; Mundy. 2003). Tumor cells activate
osteoclasts, which cause excessive bone resorption leading to bone
lesions and subsequently skeletal complications. It is worth noting the
osteolytic process is also active in the osteoblastic lesions as
evidenced by increased bone resorption markers in patients with
osteoblastic lesions (Demers et al, 2000), and an increase in the number
of osteoclasts at sites of invasion by prostate cancer cell into the
bone (Yonou et al, 2004). Zometa acts primarily by inhibiting
osteoclasts by inducing apoptosis and preventing the maturation and
activation of osteoclasts, thus causing suppression of bone resorption
(Green 2002).

Bone lesions occur in almost all patients with Durie-Salmon stage III
multiple myeloma and in the majority of patients with advanced breast or
prostate cancer, where bone metastases occur in 65-75% of the patients
(Coleman 1997, Coleman 2002). These patients frequently experience bone
complications known as skeletal related events (SREs), which include
pathological or clinical fractures, spinal cord compression, surgery to
bone and hypcercalcemia of malignancy (HCM). Approximately half of the
patients experience one or more SREs during their disease course
(Theriault 1999; Lipton 2000), which constitutes a significant clinical
problem, as the SREs are painful and sometimes debilitating
complications that can seriously limit patient mobility and cause
deterioration in patients' quality of life (Coleman 1997).

While several therapeutic options exist for the management of bone
metastases such as local radiation and systemic hormonal or
chemotherapy, patients with multiple myeloma or bone metastases
continued to experience skeletal complications prior to the introduction
of bisphosphonate, which has now become the mainstay for the prevention
of skeletal complications in these patients. Randomized clinical trials
with 90 mg pamidronate (Aredia) demonstrated significant clinical
benefit of this agent showing reduction of skeletal morbidity in
patients with multiple myeloma (Berenson et al, 1996), breast cancer
patients undergoing chemotherapy (Protocol 19, Hortobagyi et al, 1996)
or hormonal therapy (Protocol 18, Theriault et al, 1999). In the
multiple myeloma study (Protocol 12), Aredia 90 mg infused over 4 hrs
monthly for 9 cycles reduced the proportion of patients with any SRE
from 41% to 24%, significantly delayed the time to fist SRE, decreased
patient's pain scores, and maintained the quality of life in these
patients (Berenson et al, 1996). In the breast cancer trials (Protocol
18 and 19), Aredia 90 mg infused over 2 hrs for 12 cycles also reduced
the proportion of patients with any SREs from 65% 46% (Protocol 19) or
from 67% to 56% (Protocol 18). The treatment also significantly delayed
the time to first SRE by nearly 7 months (P19) or 3 months (P18). Both
studies demonstrated a decrease in patient's pain scores and analgesic
consumption, and \[Study 0019\] also showed a better ECOG performance
status in the Aredia group than the placebo group (Hortobagyi 1996,
Hortobagyi 1998; Theriault 1999, Clinical Study Report for P18 and P19
-- core+extension). Data from these clinical trials established Aredia
as the standard of care for patients with multiple myeloma bone
metastases from breast cancer with bone metastases as recommended by
ASCO guidelines (Hillner 2000, Hillner 2003; Berenson 2002).

The phase III program for Zometa consists of 3 large randomized clinical
trial involving \> 3,000 patients with multiple myeloma or breast cancer
\[Study 0010\], prostate cancer \[Study 0039\], or lung cancer and other
solid tumors \[Study 0011\]. These trials were the basis for documenting
effectiveness in bone metastases that led to its marketing authorization
globally. \[Study 0010\] demonstrates that 4 mg Zometa infused over 15
min every 3-4 weeks was at least as effective as 90 mg Aredia in terms
of proportion of patients with any SREs (Rosen et al, 2001). Exploratory
multiple-event analyses with the Anderson-Gill approach suggested that
Zometa reduces the risk of developing one or more SREs by an additional
20% as compared to Aredia in the subset of patients with breast cancer
(Rosen et al, 2003a). Furthermore, a retrospective analysis of \[Study
0010\] in the subset of breast cancer patients with one or more lytic
lesions indicated that Zometa is more effective than Aredia in this
patient population, reducing the proportion of patients with any SRE by
an additional 10% (48% for Zometa and 58% for Aredia patients, p=0.058);
and reducing the risk of developing one or more SREs by an additional
30% in comparison with Aredia (p=0.01) (Rosen et al, 2004).

Clinical trials with Zometa have also demonstrated for the first time
that the efficacy of a bisphosphonate in prostate cancer (Saad et al,
2002). Clinical trials for Aredia failed to demonstrate clinical benefit
in this patient population (Small et al, 2003), where Zometa was shown
to reduce the proportion of patients with any SRE from 49% to 38%, and
delay the time to first SRE by more than 5 months (Saad et al, 2004). In
patients with in lung cancer and solid tumors other than breast or
prostate cancer, Zometa reduced the proportion of patients with SRE from
46% to 39%, and delayed the time to first SRE by more than 2 months
(\[Study 0011\], Rosen et al, 2003b). Additionally, these trials show
that Zometa significantly reduced the risk of developing one or more
SREs by \>30% in these patients (Saad 2004, Rosen 2003b). The key
efficacy data of the placebo-controlled trials are shown in Table 2-1
and Table 2-2.

In summary, the clinical trials of Zometa clearly demonstrate its
efficacy in patients with multiple myleoma and bone metastases from
solid tumors. The clinical data not only show that Zometa is at least as
effective as Aredia in multiple myeloma and breast cancer, but also
suggest that Zometa may be more effective than Aredia for patients with
breast cancer, particularly those with lytic lesions. Moreover, Zometa
demonstrated efficacy in prostate cancer where Aredia failed to show
efficacy, as well as in lung cancer and other solid tumors where Aredia
has not been investigated in clinical trials. Thus, Zometa has expanded
the spectrum of clinical activity of bisphosphonates, and offers
additional benefit to patient populations previously not treated with
bisphosphonates. Together with the convenience of a 15 minute infusion,
Zometa provides significant clinical benefit to patients with a wide
range of malignancies, which has enabled Zometa as the new standard of
care for patients with bone lesions from malignancies. Today, Zometa is
the most widely used bisphosphonate in oncology.

###### Table 2-1 Efficacy summary of Zometa in patients with prostate cancer \[Study 0039\] {#table-2-1-efficacy-summary-of-zometa-in-patients-with-prostate-cancer-study-0039 .unnumbered}

+--------------+------------+--------------+------------+------------+
|              | **         | **Time to    | **Mean     | **Mult     |
|              | Proportion | first SRE,   | skeletal   | iple-event |
|              | of         | median days\ | morbidity  | analysis,\ |
|              | patients   | (hazard      | rate,      | hazard     |
|              | with an    | ratio)\*\*** | events/    | r          |
|              | SRE, %\*** |              | year\*\*** | atio\*\*** |
+--------------+------------+--------------+------------+------------+
| ZOMETA 4 mg\ | 38         | 488 (0.677)  | 0.77       | 0.64       |
| N = 214      |            |              |            |            |
+--------------+------------+--------------+------------+------------+
| Placebo\     | 49         | 321          | 1.47       |            |
| N = 208      |            |              |            |            |
+--------------+------------+--------------+------------+------------+
| *P* value    | 0.028      | 0.009        | 0.005      | 0.002      |
+--------------+------------+--------------+------------+------------+
| \*H          |            |              |            |            |
| ypercalcemia |            |              |            |            |
| of           |            |              |            |            |
| malignancy   |            |              |            |            |
| (HCM)        |            |              |            |            |
| excluded as  |            |              |            |            |
| an SRE       |            |              |            |            |
|              |            |              |            |            |
| \*\*HCM      |            |              |            |            |
| included as  |            |              |            |            |
| an SRE       |            |              |            |            |
+--------------+------------+--------------+------------+------------+

###### Table 2-2 Efficacy summary of Zometa in patients with lung cancer and other solid tumors \[Study 0011\] {#table-2-2-efficacy-summary-of-zometa-in-patients-with-lung-cancer-and-other-solid-tumors-study-0011 .unnumbered}

+--------------+------------+--------------+------------+------------+
|              | **         | **Time to    | **Mean     | **Multiple |
|              | Proportion | first SRE,   | skeletal   | event      |
|              | of         | median days\ | morbidity  | analysis,\ |
|              | patients   | (hazard      | rate,      | hazard     |
|              | with an    | ratio)\*\*** | events/    | r          |
|              | SRE, %\*** |              | year\*\*** | atio\*\*** |
+--------------+------------+--------------+------------+------------+
| ZOMETA 4 mg\ | 39         | 236 (0.703)  | 1.74       | 0.693      |
| N = 257      |            |              |            |            |
+--------------+------------+--------------+------------+------------+
| Placebo\     | 46         | 155          | 2.71       |            |
| N = 250      |            |              |            |            |
+--------------+------------+--------------+------------+------------+
| *P* value    | 0.127      | 0.009        | 0.012      | 0.003      |
+--------------+------------+--------------+------------+------------+
| \*HCM        |            |              |            |            |
| excluded as  |            |              |            |            |
| an SRE       |            |              |            |            |
|              |            |              |            |            |
| \*\*HCM      |            |              |            |            |
| included as  |            |              |            |            |
| an SRE       |            |              |            |            |
+--------------+------------+--------------+------------+------------+

# Osteonecrosis (ON) -- background information

## Introduction

Osteonecrosis (ON), also known as aseptic vascular necrosis of the bone
(AVN), refers to the death of bone, which occurs as a result of impaired
blood supply to the affected areas. Other terms that are used to
describe ON include ischemic necrosis, subchondral avascular necrosis,
aseptic necrosis of bone, and osteochondritis dissecans (Assouline-Dayan
et al, 2002). ON can occur in multiple locations of the skeleton, but
the femoral head appears to be the most frequently involved site.
Reports of ON at other sites such as humerus, shoulder, knee, as well as
the jaw bone have been reported. Patients with ON usually present with
pain, bone destruction, and functional disability. Diagnosis of ON is
based on clinical findings and imaging studies using MRI, X-ray film,
and sometimes bone scan. No curative treatment exists for ON, which is
usually managed with either conservative anti-inflammatory treatment or
surgery.

The causes of ON include trauma and non-traumatic factors that lead to
interruption of circulation to bone. The mechanism for the reduction or
loss of blood supply to the involved areas of bone includes intraluminal
obstruction (thromboembolism, sludging of blood cells, or stasis),
vascular compression (vasospasm), and the physical disruption of the
vessel (Wolfe et al, 2000). It is estimated that non-traumatic ON occurs
at an incidence of \~ 10,000 to 20,000 new cases per year in the US
(Mankin 1992). While the etiology and pathogenesis of ON are not well
understood (Bouquot 2000; Wang 2003), a variety of medical conditions
and a large number of risk factors have been associated with ON (Vail
and Covington 1997), suggesting that the etiology of ON is
multifactorial.

## Risk factors for ON

Numerous medical conditions and risk factors have been associated with
ON (Appendix 1), including several uncommon diseases such as connective
tissue disorders, sickle-cell disease, Gaucher's disease, systemic lupus
erythematosus (SLE) as well as some common medical conditions such as
direct or indirect trauma, infection, coagulopathy, hyperlipidemia,
anemia, immunocompromised states (e.g., HIV infection), and cancer
(Jones 1997; Assouline-Dayan 2002). The pathogenetic pathways underlying
the development of ON in patients with these conditions is complicated
and not clear, but eventually the risk factors lead to compromised
circulation to areas of the bone with subsequent death and necrosis of
the involved area. Published literature suggests intravascular
coagulation (IC) as a common intermediary event in the pathway leading
to ON, as evidenced by a study showing that 82% of ON patients evaluated
had at least one coagulation abnormality as compared to 30% of the
controls (Jones et al, 2003). Therefore, defects in the coagulation
mechanism may have some impact on the development of ON, as discussed in
case reports of hypercoagulability in ON patients resulting from
thrombophilia or hypofibrinolysis (Cheras 1997, Zalavras 2002).

ON has been associated with various drugs, notably, alcohol abuse,
smoking and corticosteroids. Alcohol has clearly been associated with
increased risk of ON with an odds ratio of \> 13 for regular drinkers
(Hirota et al, 1997). Similarly, smoking increases the risk of ON by \>
4 fold (Hirota et al, 1997). Alcohol causes disturbances of circulation
by inducing fat embolism, while smoking has been shown to have negative
impact on the cardiovascular system, both of which could lead to
vascular occlusion and development of ON (Hirota et al, 1997).

### Corticosteroids as a risk factor for ON

Corticosteroids are a known risk factor for ON (Gebhard and Maibach
2001). In a study with patients on corticosteroid replacement therapy,
ON occurred in 2.4% of the patients with a latency of 16 months to five
years (Vreden et al, 1991). ON has also been reported in patients
exposed to topical corticosteroids (Kubo 2001; Mistlin 2004), indicating
a strong association of this risk factor with ON. In patients undergoing
organ transplant, a rate of ON as high as 41% post-transplant was
reported in an earlier literature (Hawking 1976), although recent
reports quoted a lower rate of 4% occurring in patients within 6 months
of a renal transplant (Lopez-Ben et al, 2004). The exact mode of action
for corticosteroids to induce ON has not been fully investigated,
although preclinical studies have shown that high-dose corticosteroids
decrease blood flow and induce hypercoagulability, causing a decrease in
blood flow to the bone (Drescher et al, 2004).

### Coagulopathy as a risk factor for ON

Another risk factor for ON, especially in cancer patients, is the
possible role of coagulopathy, which is known to occur commonly in
cancer patients. Coagulopathy may manifest as venous thromboembolism
(VTE) or deep vein thrombosis (DVT) (Baron 1998, Kakkar 2004, Zangari
2004). Glueck and colleagues have documented thrombophilia and
hypofibrinolysis in several cohorts of patients with ON of the hip,
which showed coagulopathy in \~ 75% of these ON patients (Glueck et al,
1997).

While one prominent risk factor or condition may be associated with the
occurrence of ON in a particular patient, studies have shown that
co-existence of multiple risk factors/conditions lead to a significantly
higher incidence of ON. For example, ON developed in 44% of systemic
lupus erythematosus (SLE) patients within 5 months of starting high dose
steroid therapy (Oinuma et al, 2001).

## ON in cancer patients

The incidence of ON in cancer patients has not been reported in the
literature. Analysis of the UK General Practice Research Database (GPRD)
by Novartis scientists suggests that the incidence of ON in cancer
patients is estimated to be 1.31 per 10,000 person-yrs (95% CI:
0.72-2.21), which is more than four times that of general population.
(Sablinkska 2003).

Risk factors for ON that are specific to cancer patients include cancer
itself, radiation therapy, chemotherapy and therapeutic regimens that
contain corticosteroids. Additionally, many cancer treatments can
compromise patients' immune systems, rendering them more susceptible to
infection. Malignancy itself is noted among the list of medical
conditions that predispose patients to ON (Appendix 1).

Various reports of ON in cancer patients have been published with
chemotherapy and steroids noted as possible risk factors (Dawson 2001,
Winquist 2001, van den Berkmortel 2004, Cook 2001, Gogas 1996). Winquist
et al (2001) summarized 15 published reports with a total of 41 cases of
ON in cancer patients treated with a variety of chemotherapy regimens
(Table 3-1), suggesting a possible role of chemotherapy in ON. It is
noteworthy that the majority of these cases of ON involves the femoral
head.

###### Table 3-3 Cases of osteonecrosis after chemotherapy for solid tumors (from Winquist et al, 2001) {#table-3-3-cases-of-osteonecrosis-after-chemotherapy-for-solid-tumors-from-winquist-et-al-2001 .unnumbered}

+-----------+-----+-----------+---------------+--------+------------+
| **Author  | **  | **Cancer  | *             | **O    | **Sites of |
| (ref.)**  | No. | di        | *Chemotherapy | nset** | ON**       |
|           | of  | agnosis** | regimen(s)**  |        |            |
|           | c   |           |               |        |            |
|           | ase |           |               |        |            |
|           | s** |           |               |        |            |
+===========+=====+===========+===============+========+============+
| Obrist et | 1\* | Breast    | CMF           | Sub    | Humeral    |
| al        |     |           |               | acute‡ | head       |
+-----------+-----+-----------+---------------+--------+------------+
| Perloff   | 2   | Breast    | CMFVP         | D      | Femoral    |
| et al     |     |           |               | elayed | heads      |
|           |     | Breast    | CMFVP         |        |            |
|           |     |           |               | D      | Femoral    |
|           |     |           |               | elayed | head       |
+-----------+-----+-----------+---------------+--------+------------+
| Harper et | 1\* | Testis    | VeB + VAC,    | Su     | Multiple   |
| al        |     |           | PVB           | bacute | including  |
|           |     |           |               |        |            |
|           |     |           |               |        | femoral    |
|           |     |           |               |        | head       |
+-----------+-----+-----------+---------------+--------+------------+
| Ishii et  | 2   | Neur      | Cycl          | Su     | Femoral    |
| al        | \*† | oblastoma | ophosphamide, | bacute | head       |
|           |     |           |               |        |            |
|           |     | Neur      | cisplat       | Su     | Femoral    |
|           |     | oblastoma | in+teniposide | bacute | head       |
|           |     |           |               |        |            |
|           |     |           | VAC           |        |            |
+-----------+-----+-----------+---------------+--------+------------+
| Marymont  | 1\* | Breast,   | FAC,          | D      | Femoral    |
| et al     |     |           | Melphalan     | elayed | condyles   |
+-----------+-----+-----------+---------------+--------+------------+
| Kolin et  | 1   | Breast    | CMFVP         | D      | Femoral    |
| al        |     |           |               | elayed | head       |
+-----------+-----+-----------+---------------+--------+------------+
| M         | 2   | Testis    | PVB           | D      | Femoral    |
| eneghello |     |           |               | elayed | heads      |
| et al     |     | Ost       | VAC           |        |            |
|           |     | eosarcoma |               | D      | Femoral    |
|           |     |           |               | elayed | heads      |
+-----------+-----+-----------+---------------+--------+------------+
|           |     |           |               |        |            |
+-----------+-----+-----------+---------------+--------+------------+
| Wuisman   | 1   | Ost       | Multiple      | Acute  | Proximal   |
| et al     |     | eosarcoma | including     |        | tibia      |
|           |     |           |               |        |            |
|           |     |           | i             |        |            |
|           |     |           | ntra-arterial |        |            |
|           |     |           | cisplatin     |        |            |
+-----------+-----+-----------+---------------+--------+------------+
|           |     |           |               |        |            |
+-----------+-----+-----------+---------------+--------+------------+
| Forrai et | 19  | Testis    | PVB           | Su     | Femoral    |
| al        |     |           |               | bacute | head (6)   |
|           |     |           |               | (2)    |            |
|           |     |           |               |        | Femoral    |
|           |     |           |               | D      | head(13)   |
|           |     |           |               | elayed |            |
|           |     |           |               | (17)   |            |
+-----------+-----+-----------+---------------+--------+------------+
| Jones     | 1   | Small     | EC, EP        | Su     | Multiple   |
|           |     | cell lung |               | bacute | including  |
|           |     |           |               |        | femoral    |
|           |     |           |               |        | head       |
+-----------+-----+-----------+---------------+--------+------------+
| Gogas et  | 1   | Ovarian   | Multiple      | D      | Femoral    |
| al        |     |           |               | elayed | heads      |
+-----------+-----+-----------+---------------+--------+------------+
| Besson et | 1   | Breast    | Multiple      | Su     | Humeral    |
| al        |     |           |               | bacute | head,      |
|           |     |           |               |        | femoral    |
|           |     |           |               |        | heads      |
+-----------+-----+-----------+---------------+--------+------------+
| Geetha et | 1   | Neur      | CAPE          | Su     | Femoral    |
| al        | \*† | oblastoma |               | bacute | heads      |
+-----------+-----+-----------+---------------+--------+------------+
| Cook et   | 5   | Testis    | BEP           | D      | Femoral    |
| al        |     |           |               | elayed | head       |
|           |     | Testis    | BEP           |        |            |
|           |     |           |               | D      | Femoral    |
|           |     | Testis    | BEP           | elayed | head       |
|           |     |           |               |        |            |
|           |     |           |               | D      | Femoral    |
|           |     |           |               | elayed | heads      |
+-----------+-----+-----------+---------------+--------+------------+
| Winquist  | 2   | Testis    | PVB           | D      | Femoral    |
| et al     |     |           |               | elayed | heads      |
|           |     | Testis    | BEP           |        |            |
|           |     |           |               | D      | Femoral    |
|           |     |           |               | elayed | heads      |
+-----------+-----+-----------+---------------+--------+------------+
| BEP,      |     |           |               |        |            |
| b         |     |           |               |        |            |
| leomycin, |     |           |               |        |            |
| e         |     |           |               |        |            |
| toposide, |     |           |               |        |            |
| c         |     |           |               |        |            |
| isplatin; |     |           |               |        |            |
| CAPE,     |     |           |               |        |            |
| cyclopho  |     |           |               |        |            |
| sphamide, |     |           |               |        |            |
| dox       |     |           |               |        |            |
| orubicin, |     |           |               |        |            |
| c         |     |           |               |        |            |
| isplatin, |     |           |               |        |            |
| e         |     |           |               |        |            |
| toposide; |     |           |               |        |            |
| CMF,      |     |           |               |        |            |
| cyclopho  |     |           |               |        |            |
| sphamide, |     |           |               |        |            |
| meth      |     |           |               |        |            |
| otrexate, |     |           |               |        |            |
| fluo      |     |           |               |        |            |
| rouracil; |     |           |               |        |            |
| CMFVP,    |     |           |               |        |            |
| cyclopho  |     |           |               |        |            |
| sphamide, |     |           |               |        |            |
| meth      |     |           |               |        |            |
| otrexate, |     |           |               |        |            |
| fluo      |     |           |               |        |            |
| rouracil, |     |           |               |        |            |
| vin       |     |           |               |        |            |
| cristine, |     |           |               |        |            |
| pr        |     |           |               |        |            |
| ednisone; |     |           |               |        |            |
| EC,       |     |           |               |        |            |
| e         |     |           |               |        |            |
| toposide, |     |           |               |        |            |
| car       |     |           |               |        |            |
| boplatin; |     |           |               |        |            |
| EP,       |     |           |               |        |            |
| etoposide |     |           |               |        |            |
| and       |     |           |               |        |            |
| c         |     |           |               |        |            |
| isplatin; |     |           |               |        |            |
| FAC,      |     |           |               |        |            |
| fluo      |     |           |               |        |            |
| rouracil, |     |           |               |        |            |
| dox       |     |           |               |        |            |
| orubicin, |     |           |               |        |            |
| cyclopho  |     |           |               |        |            |
| sphamide; |     |           |               |        |            |
| PVB,      |     |           |               |        |            |
| c         |     |           |               |        |            |
| isplatin, |     |           |               |        |            |
| vin       |     |           |               |        |            |
| blastine, |     |           |               |        |            |
| b         |     |           |               |        |            |
| leomycin; |     |           |               |        |            |
| VAC,      |     |           |               |        |            |
| vin       |     |           |               |        |            |
| cristine, |     |           |               |        |            |
|           |     |           |               |        |            |
| dact      |     |           |               |        |            |
| inomycin, |     |           |               |        |            |
| cyclopho  |     |           |               |        |            |
| sphamide; |     |           |               |        |            |
| VeB,      |     |           |               |        |            |
| vin       |     |           |               |        |            |
| blastine, |     |           |               |        |            |
| b         |     |           |               |        |            |
| leomycin. |     |           |               |        |            |
|           |     |           |               |        |            |
| \*        |     |           |               |        |            |
| Che       |     |           |               |        |            |
| motherapy |     |           |               |        |            |
| given     |     |           |               |        |            |
| without   |     |           |               |        |            |
| cortico   |     |           |               |        |            |
| steroids. |     |           |               |        |            |
|           |     |           |               |        |            |
| †         |     |           |               |        |            |
| Pediatric |     |           |               |        |            |
| patient.  |     |           |               |        |            |
|           |     |           |               |        |            |
| ‡         |     |           |               |        |            |
| Subacute, |     |           |               |        |            |
| diagnosis |     |           |               |        |            |
| of        |     |           |               |        |            |
| oste      |     |           |               |        |            |
| onecrosis |     |           |               |        |            |
| nonacute  |     |           |               |        |            |
| duri      |     |           |               |        |            |
| ng/within |     |           |               |        |            |
| 6 months  |     |           |               |        |            |
| of        |     |           |               |        |            |
| chem      |     |           |               |        |            |
| otherapy. |     |           |               |        |            |
+-----------+-----+-----------+---------------+--------+------------+
| Obrist R, |     |           |               |        |            |
| Hartmann  |     |           |               |        |            |
| D and     |     |           |               |        |            |
| Obrecht   |     |           |               |        |            |
| JP (1978) |     |           |               |        |            |
| Oste      |     |           |               |        |            |
| onecrosis |     |           |               |        |            |
| after     |     |           |               |        |            |
| che       |     |           |               |        |            |
| motherapy |     |           |               |        |            |
| \[        |     |           |               |        |            |
| letter\]. |     |           |               |        |            |
| Lancet;   |     |           |               |        |            |
| 1:1316.   |     |           |               |        |            |
|           |     |           |               |        |            |
| Perloff M |     |           |               |        |            |
| and       |     |           |               |        |            |
| Lesnick   |     |           |               |        |            |
| GJ (1980) |     |           |               |        |            |
| Avascular |     |           |               |        |            |
| necrosis  |     |           |               |        |            |
| of the    |     |           |               |        |            |
| femoral   |     |           |               |        |            |
| head:     |     |           |               |        |            |
| as        |     |           |               |        |            |
| sociation |     |           |               |        |            |
| with      |     |           |               |        |            |
| adjuvant  |     |           |               |        |            |
| che       |     |           |               |        |            |
| motherapy |     |           |               |        |            |
| for       |     |           |               |        |            |
| breast    |     |           |               |        |            |
| c         |     |           |               |        |            |
| arcinoma. |     |           |               |        |            |
| Cancer    |     |           |               |        |            |
| Treat     |     |           |               |        |            |
| Rep;      |     |           |               |        |            |
| 6         |     |           |               |        |            |
| 4:361--2. |     |           |               |        |            |
|           |     |           |               |        |            |
| Harper    |     |           |               |        |            |
| PG, Trask |     |           |               |        |            |
| C and     |     |           |               |        |            |
| Souhami   |     |           |               |        |            |
| RL (1984) |     |           |               |        |            |
| Avascular |     |           |               |        |            |
| necrosis  |     |           |               |        |            |
| of bone   |     |           |               |        |            |
| caused by |     |           |               |        |            |
| co        |     |           |               |        |            |
| mbination |     |           |               |        |            |
| che       |     |           |               |        |            |
| motherapy |     |           |               |        |            |
| without   |     |           |               |        |            |
| cortico   |     |           |               |        |            |
| steroids. |     |           |               |        |            |
| BMJ (Clin |     |           |               |        |            |
| Res);     |     |           |               |        |            |
| 28        |     |           |               |        |            |
| 8:267--8. |     |           |               |        |            |
|           |     |           |               |        |            |
| Ishii E,  |     |           |               |        |            |
| Yoshida N |     |           |               |        |            |
| and       |     |           |               |        |            |
| Miyazaki  |     |           |               |        |            |
| S (1984)  |     |           |               |        |            |
| Avascular |     |           |               |        |            |
| necrosis  |     |           |               |        |            |
| of bone   |     |           |               |        |            |
| in        |     |           |               |        |            |
| neur      |     |           |               |        |            |
| oblastoma |     |           |               |        |            |
| treated   |     |           |               |        |            |
| with      |     |           |               |        |            |
| co        |     |           |               |        |            |
| mbination |     |           |               |        |            |
| chem      |     |           |               |        |            |
| otherapy. |     |           |               |        |            |
| Eur J     |     |           |               |        |            |
| Pediatr;  |     |           |               |        |            |
| 14        |     |           |               |        |            |
| 3:152--3. |     |           |               |        |            |
|           |     |           |               |        |            |
| Marymont  |     |           |               |        |            |
| JV and    |     |           |               |        |            |
| Kaufman   |     |           |               |        |            |
| EE (1986) |     |           |               |        |            |
| Oste      |     |           |               |        |            |
| onecrosis |     |           |               |        |            |
| of bone   |     |           |               |        |            |
| a         |     |           |               |        |            |
| ssociated |     |           |               |        |            |
| with      |     |           |               |        |            |
| co        |     |           |               |        |            |
| mbination |     |           |               |        |            |
| che       |     |           |               |        |            |
| motherapy |     |           |               |        |            |
| without   |     |           |               |        |            |
| cortico   |     |           |               |        |            |
| steroids. |     |           |               |        |            |
| Clin      |     |           |               |        |            |
| Orthop;   |     |           |               |        |            |
| 20        |     |           |               |        |            |
| 4:150--3. |     |           |               |        |            |
|           |     |           |               |        |            |
| Kolin E   |     |           |               |        |            |
| and       |     |           |               |        |            |
| Sherry H  |     |           |               |        |            |
| (1987)    |     |           |               |        |            |
| Avascular |     |           |               |        |            |
| necrosis  |     |           |               |        |            |
| of the    |     |           |               |        |            |
| femoral   |     |           |               |        |            |
| head in   |     |           |               |        |            |
| patients  |     |           |               |        |            |
| being     |     |           |               |        |            |
| treated   |     |           |               |        |            |
| for       |     |           |               |        |            |
| ma        |     |           |               |        |            |
| lignancy. |     |           |               |        |            |
| Mt Sinai  |     |           |               |        |            |
| J Med;    |     |           |               |        |            |
| 54:       |     |           |               |        |            |
| 516--21.  |     |           |               |        |            |
|           |     |           |               |        |            |
| M         |     |           |               |        |            |
| eneghello |     |           |               |        |            |
| A,        |     |           |               |        |            |
| Presacco  |     |           |               |        |            |
| D and Di  |     |           |               |        |            |
| Maggio C  |     |           |               |        |            |
| (1989)    |     |           |               |        |            |
| Aseptic   |     |           |               |        |            |
| necrosis  |     |           |               |        |            |
| of the    |     |           |               |        |            |
| femoral   |     |           |               |        |            |
| head in   |     |           |               |        |            |
| cancer    |     |           |               |        |            |
| patients  |     |           |               |        |            |
| affected  |     |           |               |        |            |
| with      |     |           |               |        |            |
| vincr     |     |           |               |        |            |
| istine/vi |     |           |               |        |            |
| nblastine |     |           |               |        |            |
| --induced |     |           |               |        |            |
| n         |     |           |               |        |            |
| europathy |     |           |               |        |            |
| \[in      |     |           |               |        |            |
| I         |     |           |               |        |            |
| talian\]. |     |           |               |        |            |
| Radiol    |     |           |               |        |            |
| Med       |     |           |               |        |            |
| (Torino); |     |           |               |        |            |
| 77        |     |           |               |        |            |
| :626--30. |     |           |               |        |            |
|           |     |           |               |        |            |
| Wuisman   |     |           |               |        |            |
| P,        |     |           |               |        |            |
| Erlemann  |     |           |               |        |            |
| R,        |     |           |               |        |            |
| Roessner  |     |           |               |        |            |
| A, et al  |     |           |               |        |            |
| (1991)    |     |           |               |        |            |
| Case      |     |           |               |        |            |
| report    |     |           |               |        |            |
| 669.      |     |           |               |        |            |
| Skeletal  |     |           |               |        |            |
| Radiol;   |     |           |               |        |            |
| 2         |     |           |               |        |            |
| 0:294--8. |     |           |               |        |            |
|           |     |           |               |        |            |
| Forrai G, |     |           |               |        |            |
| Baki M    |     |           |               |        |            |
| and       |     |           |               |        |            |
| Bodrogi I |     |           |               |        |            |
| (1994)    |     |           |               |        |            |
| Incidence |     |           |               |        |            |
| of        |     |           |               |        |            |
| ost       |     |           |               |        |            |
| eoporosis |     |           |               |        |            |
| and       |     |           |               |        |            |
| aseptic   |     |           |               |        |            |
| femoral   |     |           |               |        |            |
| head      |     |           |               |        |            |
| necrosis  |     |           |               |        |            |
| after     |     |           |               |        |            |
| complex   |     |           |               |        |            |
| c         |     |           |               |        |            |
| ytostatic |     |           |               |        |            |
| therapy   |     |           |               |        |            |
| in germ   |     |           |               |        |            |
| cell      |     |           |               |        |            |
| t         |     |           |               |        |            |
| esticular |     |           |               |        |            |
| cancer    |     |           |               |        |            |
| patients  |     |           |               |        |            |
| \[in      |     |           |               |        |            |
| Hun       |     |           |               |        |            |
| garian\]. |     |           |               |        |            |
| Orv       |     |           |               |        |            |
| Hetil;    |     |           |               |        |            |
| 135:      |     |           |               |        |            |
| 1         |     |           |               |        |            |
| 695--700. |     |           |               |        |            |
|           |     |           |               |        |            |
| Jones DN  |     |           |               |        |            |
| (1994)    |     |           |               |        |            |
| M         |     |           |               |        |            |
| ultifocal |     |           |               |        |            |
| oste      |     |           |               |        |            |
| onecrosis |     |           |               |        |            |
| following |     |           |               |        |            |
| che       |     |           |               |        |            |
| motherapy |     |           |               |        |            |
| and       |     |           |               |        |            |
| s         |     |           |               |        |            |
| hort-term |     |           |               |        |            |
| corti     |     |           |               |        |            |
| costeroid |     |           |               |        |            |
| therapy   |     |           |               |        |            |
| in a      |     |           |               |        |            |
| patient   |     |           |               |        |            |
| with      |     |           |               |        |            |
| s         |     |           |               |        |            |
| mall-cell |     |           |               |        |            |
| ro        |     |           |               |        |            |
| nchogenic |     |           |               |        |            |
| c         |     |           |               |        |            |
| arcinoma. |     |           |               |        |            |
| J Nucl    |     |           |               |        |            |
| Med;      |     |           |               |        |            |
| 35:       |     |           |               |        |            |
| 1347--50. |     |           |               |        |            |
|           |     |           |               |        |            |
| Gogas H   |     |           |               |        |            |
| and       |     |           |               |        |            |
| Fennelly  |     |           |               |        |            |
| D (1996)  |     |           |               |        |            |
| Avascular |     |           |               |        |            |
| necrosis  |     |           |               |        |            |
| following |     |           |               |        |            |
| extensive |     |           |               |        |            |
| che       |     |           |               |        |            |
| motherapy |     |           |               |        |            |
| and       |     |           |               |        |            |
| dexa      |     |           |               |        |            |
| methasone |     |           |               |        |            |
| treatment |     |           |               |        |            |
| in a      |     |           |               |        |            |
| patient   |     |           |               |        |            |
| with      |     |           |               |        |            |
| advanced  |     |           |               |        |            |
| ovarian   |     |           |               |        |            |
| cancer:   |     |           |               |        |            |
| case      |     |           |               |        |            |
| report    |     |           |               |        |            |
| and       |     |           |               |        |            |
| review of |     |           |               |        |            |
| the       |     |           |               |        |            |
| li        |     |           |               |        |            |
| terature. |     |           |               |        |            |
| Gynecol   |     |           |               |        |            |
| Oncol;    |     |           |               |        |            |
| 63        |     |           |               |        |            |
| :379--81. |     |           |               |        |            |
|           |     |           |               |        |            |
| Besson C, |     |           |               |        |            |
| St        |     |           |               |        |            |
| elianides |     |           |               |        |            |
| S,        |     |           |               |        |            |
| Belmatoug |     |           |               |        |            |
| N, et al  |     |           |               |        |            |
| (1998)    |     |           |               |        |            |
| M         |     |           |               |        |            |
| ultifocal |     |           |               |        |            |
| oste      |     |           |               |        |            |
| onecrosis |     |           |               |        |            |
| after     |     |           |               |        |            |
| che       |     |           |               |        |            |
| motherapy |     |           |               |        |            |
| in a      |     |           |               |        |            |
| patient   |     |           |               |        |            |
| with      |     |           |               |        |            |
| breast    |     |           |               |        |            |
| cancer. J |     |           |               |        |            |
| R         |     |           |               |        |            |
| heumatol; |     |           |               |        |            |
| 25:       |     |           |               |        |            |
| 2479--80. |     |           |               |        |            |
|           |     |           |               |        |            |
| Geetha N, |     |           |               |        |            |
| Kumary    |     |           |               |        |            |
| PK,       |     |           |               |        |            |
| Ram       |     |           |               |        |            |
| achandran |     |           |               |        |            |
| K, et al  |     |           |               |        |            |
| (1998)    |     |           |               |        |            |
| Avascular |     |           |               |        |            |
| necrosis  |     |           |               |        |            |
| of the    |     |           |               |        |            |
| femoral   |     |           |               |        |            |
| head in   |     |           |               |        |            |
| neuro     |     |           |               |        |            |
| blastoma: |     |           |               |        |            |
| a case    |     |           |               |        |            |
| report.   |     |           |               |        |            |
| Pediatr   |     |           |               |        |            |
| Hematol   |     |           |               |        |            |
| Oncol;    |     |           |               |        |            |
| 1         |     |           |               |        |            |
| 5:443--6. |     |           |               |        |            |
|           |     |           |               |        |            |
| Cook AM,  |     |           |               |        |            |
| Patterson |     |           |               |        |            |
| H,        |     |           |               |        |            |
| Nicholls  |     |           |               |        |            |
| J, et al  |     |           |               |        |            |
| (1999)    |     |           |               |        |            |
| Avascular |     |           |               |        |            |
| necrosis  |     |           |               |        |            |
| in        |     |           |               |        |            |
| patients  |     |           |               |        |            |
| treated   |     |           |               |        |            |
| with BEP  |     |           |               |        |            |
| che       |     |           |               |        |            |
| motherapy |     |           |               |        |            |
| for       |     |           |               |        |            |
| t         |     |           |               |        |            |
| esticular |     |           |               |        |            |
| tumours.  |     |           |               |        |            |
| Clin      |     |           |               |        |            |
| Oncol (R  |     |           |               |        |            |
| Coll      |     |           |               |        |            |
| Radiol);  |     |           |               |        |            |
| 1         |     |           |               |        |            |
| 1:126--7. |     |           |               |        |            |
|           |     |           |               |        |            |
| Winquist  |     |           |               |        |            |
| EW,       |     |           |               |        |            |
| Bauman GS |     |           |               |        |            |
| and       |     |           |               |        |            |
| Balogh J  |     |           |               |        |            |
| (2001)    |     |           |               |        |            |
| Non       |     |           |               |        |            |
| traumatic |     |           |               |        |            |
| oste      |     |           |               |        |            |
| onecrosis |     |           |               |        |            |
| after     |     |           |               |        |            |
| che       |     |           |               |        |            |
| motherapy |     |           |               |        |            |
| for       |     |           |               |        |            |
| t         |     |           |               |        |            |
| esticular |     |           |               |        |            |
| cancer: a |     |           |               |        |            |
| s         |     |           |               |        |            |
| ystematic |     |           |               |        |            |
| review.   |     |           |               |        |            |
| Am J Clin |     |           |               |        |            |
| Oncol;    |     |           |               |        |            |
| 24(       |     |           |               |        |            |
| 6):603-6. |     |           |               |        |            |
+-----------+-----+-----------+---------------+--------+------------+

Corticosteriods are key components of therapeutic regimens for
hematological malignancies such as acute lymphoblastic leukemia, and
therefore patients with these types of malignancy may be exposed to high
dose corticosteroids for prolonged periods of time. For example, the
incidence of ON is estimated to be \~ 9-20% for children and young
adults 10-20 years of age receiving intensive therapy for acute
lymphocytic leukemia using regimens that contain high dose
corticosteroids (Mattano et al, 2000). Additionally, patients undergoing
stem-cell transplant are also exposed to high-dose steroids. The
reported prevalence of ON ranges from 0.6 to 38% in patients with
various hematological malignancies as summarized by Assouline-Dayan et
al (2002) (Table 3-2).

###### Table 3-4 Selected studies of corticosteroid-induced osteonecrosis \[adapted from (Assouline-Dayan et al, 2002)\] {#table-3-4-selected-studies-of-corticosteroid-induced-osteonecrosis-adapted-from-assouline-dayan-et-al-2002 .unnumbered}

+-------+----------+------+--------+-----------+----------+-----------+
| *     | **Type   | **   | **Prev | **Gl      | **Mean   | **Re      |
| *Cond | of       | Pati | alence | ucocortic | Interval | ference** |
| ition | Study**  | ents | (%)**  | o-steroid | Between  |           |
| or    |          | (    |        | Dose**    | T        |           |
| Dise  |          | n)** |        |           | reatment |           |
| ase** |          |      |        |           | and      |           |
|       |          |      |        |           | Osteone  |           |
|       |          |      |        |           | crosis** |           |
+-------+----------+------+--------+-----------+----------+-----------+
| ALL   | Pro      | 24   | 38     | NA        | Within a | (Ojala et |
|       | spective |      |        |           | few      | al        |
|       |          |      |        |           | months   | 1999)^1^  |
+-------+----------+------+--------+-----------+----------+-----------+
| Post- | Retro    | 272  | 6      | Total     | 13       | (Weismann |
| allog | spective |      |        | dose 189  |          | et al     |
| eneic |          |      |        | mg/kg     |          | 1998)^2^  |
| BMT   |          |      |        | (range    |          |           |
|       |          |      |        | 13-555    |          |           |
|       |          |      |        | mg/kg)    |          |           |
+-------+----------+------+--------+-----------+----------+-----------+
| Hodg  | Retro    | 784  | 1      | Total     | 35       | (Enrici   |
| kin's | spective |      |        | P         |          | et al     |
| Di    |          |      |        | rednisone |          | 1998)^3^  |
| sease |          |      |        | 27        |          |           |
|       |          |      |        | 25-5250mg |          |           |
+-------+----------+------+--------+-----------+----------+-----------+
| ALL   | Retro    | 850  | 0.6    | NA        | 29       | (Vaidya   |
|       | spective |      |        |           |          | et al     |
|       |          |      |        |           |          | 1998)^4^  |
+-------+----------+------+--------+-----------+----------+-----------+
| Pos   | Case     | 1939 | 5      | NA        | 26       | (Fink et  |
| t-BMT | Control  |      |        |           |          | al        |
|       |          |      |        |           |          | 1998)^5^  |
+-------+----------+------+--------+-----------+----------+-----------+
| Pedia | Pro      | 28   | 32     | High-dose | NA       | (Ojala et |
| tric, | spective |      |        | Dexa      |          | al        |
| ALL   |          |      |        | methasone |          | 1997)^6^  |
+-------+----------+------+--------+-----------+----------+-----------+
| Pos   | Mul      | 4388 | 4      | NA        | 22       | (Socie et |
| t-BMT | ticenter |      |        |           |          | al        |
|       | Retro    |      |        |           |          | 1997)^7^  |
|       | spective |      |        |           |          |           |
+-------+----------+------+--------+-----------+----------+-----------+
| 1\.   |          |      |        |           |          |           |
| Ojala |          |      |        |           |          |           |
| AE,   |          |      |        |           |          |           |
| P     |          |      |        |           |          |           |
| aakko |          |      |        |           |          |           |
| E,    |          |      |        |           |          |           |
| La    |          |      |        |           |          |           |
| nning |          |      |        |           |          |           |
| FP,   |          |      |        |           |          |           |
| La    |          |      |        |           |          |           |
| nning |          |      |        |           |          |           |
| M     |          |      |        |           |          |           |
| (     |          |      |        |           |          |           |
| 1999) |          |      |        |           |          |           |
| Ost   |          |      |        |           |          |           |
| eonec |          |      |        |           |          |           |
| rosis |          |      |        |           |          |           |
| d     |          |      |        |           |          |           |
| uring |          |      |        |           |          |           |
| the   |          |      |        |           |          |           |
| trea  |          |      |        |           |          |           |
| tment |          |      |        |           |          |           |
| of    |          |      |        |           |          |           |
| chil  |          |      |        |           |          |           |
| dhood |          |      |        |           |          |           |
| acute |          |      |        |           |          |           |
| lym   |          |      |        |           |          |           |
| phobl |          |      |        |           |          |           |
| astic |          |      |        |           |          |           |
| leuk  |          |      |        |           |          |           |
| emia: |          |      |        |           |          |           |
| a     |          |      |        |           |          |           |
| p     |          |      |        |           |          |           |
| rospe |          |      |        |           |          |           |
| ctive |          |      |        |           |          |           |
| MRI   |          |      |        |           |          |           |
| s     |          |      |        |           |          |           |
| tudy. |          |      |        |           |          |           |
| Med   |          |      |        |           |          |           |
| Pe    |          |      |        |           |          |           |
| diatr |          |      |        |           |          |           |
| O     |          |      |        |           |          |           |
| ncol; |          |      |        |           |          |           |
| 32:   |          |      |        |           |          |           |
| 11-7. |          |      |        |           |          |           |
|       |          |      |        |           |          |           |
| 2\.   |          |      |        |           |          |           |
| Wei   |          |      |        |           |          |           |
| smann |          |      |        |           |          |           |
| A,    |          |      |        |           |          |           |
| Pe    |          |      |        |           |          |           |
| reira |          |      |        |           |          |           |
| P,    |          |      |        |           |          |           |
| Bohm  |          |      |        |           |          |           |
| P, et |          |      |        |           |          |           |
| al    |          |      |        |           |          |           |
| (     |          |      |        |           |          |           |
| 1998) |          |      |        |           |          |           |
| Avas  |          |      |        |           |          |           |
| cular |          |      |        |           |          |           |
| nec   |          |      |        |           |          |           |
| rosis |          |      |        |           |          |           |
| of    |          |      |        |           |          |           |
| bone  |          |      |        |           |          |           |
| foll  |          |      |        |           |          |           |
| owing |          |      |        |           |          |           |
| allog |          |      |        |           |          |           |
| eneic |          |      |        |           |          |           |
| stem  |          |      |        |           |          |           |
| cell  |          |      |        |           |          |           |
| t     |          |      |        |           |          |           |
| ransp |          |      |        |           |          |           |
| lanta |          |      |        |           |          |           |
| tion: |          |      |        |           |          |           |
| MR    |          |      |        |           |          |           |
| scre  |          |      |        |           |          |           |
| ening |          |      |        |           |          |           |
| and   |          |      |        |           |          |           |
| t     |          |      |        |           |          |           |
| herap |          |      |        |           |          |           |
| eutic |          |      |        |           |          |           |
| opt   |          |      |        |           |          |           |
| ions. |          |      |        |           |          |           |
| Bone  |          |      |        |           |          |           |
| M     |          |      |        |           |          |           |
| arrow |          |      |        |           |          |           |
| T     |          |      |        |           |          |           |
| ransp |          |      |        |           |          |           |
| lant; |          |      |        |           |          |           |
| 22:5  |          |      |        |           |          |           |
| 65-9. |          |      |        |           |          |           |
|       |          |      |        |           |          |           |
| 3\.   |          |      |        |           |          |           |
| E     |          |      |        |           |          |           |
| nrici |          |      |        |           |          |           |
| RM,   |          |      |        |           |          |           |
| An    |          |      |        |           |          |           |
| selmo |          |      |        |           |          |           |
| AP,   |          |      |        |           |          |           |
| D     |          |      |        |           |          |           |
| onato |          |      |        |           |          |           |
| V, et |          |      |        |           |          |           |
| al    |          |      |        |           |          |           |
| (     |          |      |        |           |          |           |
| 1998) |          |      |        |           |          |           |
| Avas  |          |      |        |           |          |           |
| cular |          |      |        |           |          |           |
| ost   |          |      |        |           |          |           |
| eonec |          |      |        |           |          |           |
| rosis |          |      |        |           |          |           |
| in    |          |      |        |           |          |           |
| pat   |          |      |        |           |          |           |
| ients |          |      |        |           |          |           |
| tr    |          |      |        |           |          |           |
| eated |          |      |        |           |          |           |
| for   |          |      |        |           |          |           |
| Hodg  |          |      |        |           |          |           |
| kin's |          |      |        |           |          |           |
| Dis   |          |      |        |           |          |           |
| ease. |          |      |        |           |          |           |
| Eur J |          |      |        |           |          |           |
| Haem  |          |      |        |           |          |           |
| atol; |          |      |        |           |          |           |
| 61:2  |          |      |        |           |          |           |
| 04-9. |          |      |        |           |          |           |
|       |          |      |        |           |          |           |
| 4\.   |          |      |        |           |          |           |
| V     |          |      |        |           |          |           |
| aidya |          |      |        |           |          |           |
| S,    |          |      |        |           |          |           |
| Saika |          |      |        |           |          |           |
| S,    |          |      |        |           |          |           |
| S     |          |      |        |           |          |           |
| irohi |          |      |        |           |          |           |
| B, et |          |      |        |           |          |           |
| al    |          |      |        |           |          |           |
| (     |          |      |        |           |          |           |
| 1998) |          |      |        |           |          |           |
| Avas  |          |      |        |           |          |           |
| cular |          |      |        |           |          |           |
| nec   |          |      |        |           |          |           |
| rosis |          |      |        |           |          |           |
| of    |          |      |        |           |          |           |
| bone  |          |      |        |           |          |           |
| -- a  |          |      |        |           |          |           |
| co    |          |      |        |           |          |           |
| mplic |          |      |        |           |          |           |
| ation |          |      |        |           |          |           |
| of    |          |      |        |           |          |           |
| aggre |          |      |        |           |          |           |
| ssive |          |      |        |           |          |           |
| th    |          |      |        |           |          |           |
| erapy |          |      |        |           |          |           |
| for   |          |      |        |           |          |           |
| acute |          |      |        |           |          |           |
| lym   |          |      |        |           |          |           |
| phobl |          |      |        |           |          |           |
| astic |          |      |        |           |          |           |
| leuk  |          |      |        |           |          |           |
| emia. |          |      |        |           |          |           |
| Acta  |          |      |        |           |          |           |
| O     |          |      |        |           |          |           |
| ncol; |          |      |        |           |          |           |
| 37:1  |          |      |        |           |          |           |
| 75-7. |          |      |        |           |          |           |
|       |          |      |        |           |          |           |
| 5\.   |          |      |        |           |          |           |
| Fink  |          |      |        |           |          |           |
| JC,   |          |      |        |           |          |           |
| Leise |          |      |        |           |          |           |
| nring |          |      |        |           |          |           |
| WM,   |          |      |        |           |          |           |
| Sul   |          |      |        |           |          |           |
| livan |          |      |        |           |          |           |
| KM,   |          |      |        |           |          |           |
| et al |          |      |        |           |          |           |
| (     |          |      |        |           |          |           |
| 1998) |          |      |        |           |          |           |
| Avas  |          |      |        |           |          |           |
| cular |          |      |        |           |          |           |
| nec   |          |      |        |           |          |           |
| rosis |          |      |        |           |          |           |
| foll  |          |      |        |           |          |           |
| owing |          |      |        |           |          |           |
| bone  |          |      |        |           |          |           |
| m     |          |      |        |           |          |           |
| arrow |          |      |        |           |          |           |
| t     |          |      |        |           |          |           |
| ransp |          |      |        |           |          |           |
| lanta |          |      |        |           |          |           |
| tion: |          |      |        |           |          |           |
| a     |          |      |        |           |          |           |
| case  |          |      |        |           |          |           |
| co    |          |      |        |           |          |           |
| ntrol |          |      |        |           |          |           |
| s     |          |      |        |           |          |           |
| tudy. |          |      |        |           |          |           |
| Bone; |          |      |        |           |          |           |
| 22:6  |          |      |        |           |          |           |
| 7-71. |          |      |        |           |          |           |
|       |          |      |        |           |          |           |
| 6\.   |          |      |        |           |          |           |
| Ojala |          |      |        |           |          |           |
| AE,   |          |      |        |           |          |           |
| La    |          |      |        |           |          |           |
| nning |          |      |        |           |          |           |
| FP,   |          |      |        |           |          |           |
| P     |          |      |        |           |          |           |
| aakko |          |      |        |           |          |           |
| E, et |          |      |        |           |          |           |
| al    |          |      |        |           |          |           |
| (     |          |      |        |           |          |           |
| 1997) |          |      |        |           |          |           |
| Ost   |          |      |        |           |          |           |
| eonec |          |      |        |           |          |           |
| rosis |          |      |        |           |          |           |
| in    |          |      |        |           |          |           |
| chi   |          |      |        |           |          |           |
| ldren |          |      |        |           |          |           |
| tr    |          |      |        |           |          |           |
| eated |          |      |        |           |          |           |
| for   |          |      |        |           |          |           |
| acute |          |      |        |           |          |           |
| lym   |          |      |        |           |          |           |
| phobl |          |      |        |           |          |           |
| astic |          |      |        |           |          |           |
| leuk  |          |      |        |           |          |           |
| emia: |          |      |        |           |          |           |
| a     |          |      |        |           |          |           |
| mag   |          |      |        |           |          |           |
| netic |          |      |        |           |          |           |
| reso  |          |      |        |           |          |           |
| nance |          |      |        |           |          |           |
| im    |          |      |        |           |          |           |
| aging |          |      |        |           |          |           |
| study |          |      |        |           |          |           |
| after |          |      |        |           |          |           |
| treat |          |      |        |           |          |           |
| ment. |          |      |        |           |          |           |
| Med   |          |      |        |           |          |           |
| Pe    |          |      |        |           |          |           |
| diatr |          |      |        |           |          |           |
| O     |          |      |        |           |          |           |
| ncol; |          |      |        |           |          |           |
| 29:2  |          |      |        |           |          |           |
| 60-5. |          |      |        |           |          |           |
|       |          |      |        |           |          |           |
| 7\.   |          |      |        |           |          |           |
| Socie |          |      |        |           |          |           |
| G,    |          |      |        |           |          |           |
| Chan  |          |      |        |           |          |           |
| JY,   |          |      |        |           |          |           |
| Ca    |          |      |        |           |          |           |
| rmelo |          |      |        |           |          |           |
| J, et |          |      |        |           |          |           |
| al    |          |      |        |           |          |           |
| (     |          |      |        |           |          |           |
| 1997) |          |      |        |           |          |           |
| Avas  |          |      |        |           |          |           |
| cular |          |      |        |           |          |           |
| nec   |          |      |        |           |          |           |
| rosis |          |      |        |           |          |           |
| of    |          |      |        |           |          |           |
| bone  |          |      |        |           |          |           |
| after |          |      |        |           |          |           |
| allog |          |      |        |           |          |           |
| eneic |          |      |        |           |          |           |
| bone  |          |      |        |           |          |           |
| m     |          |      |        |           |          |           |
| arrow |          |      |        |           |          |           |
| t     |          |      |        |           |          |           |
| ransp |          |      |        |           |          |           |
| lanta |          |      |        |           |          |           |
| tion: |          |      |        |           |          |           |
| ana   |          |      |        |           |          |           |
| lysis |          |      |        |           |          |           |
| of    |          |      |        |           |          |           |
| risk  |          |      |        |           |          |           |
| fa    |          |      |        |           |          |           |
| ctors |          |      |        |           |          |           |
| for   |          |      |        |           |          |           |
| 4388  |          |      |        |           |          |           |
| pat   |          |      |        |           |          |           |
| ients |          |      |        |           |          |           |
| by    |          |      |        |           |          |           |
| the   |          |      |        |           |          |           |
| So    |          |      |        |           |          |           |
| ciete |          |      |        |           |          |           |
| Fran  |          |      |        |           |          |           |
| caise |          |      |        |           |          |           |
| de    |          |      |        |           |          |           |
| G     |          |      |        |           |          |           |
| reffe |          |      |        |           |          |           |
| de    |          |      |        |           |          |           |
| M     |          |      |        |           |          |           |
| oelle |          |      |        |           |          |           |
| (S    |          |      |        |           |          |           |
| FGM). |          |      |        |           |          |           |
| Br J  |          |      |        |           |          |           |
| Haem  |          |      |        |           |          |           |
| atol; |          |      |        |           |          |           |
| 97:86 |          |      |        |           |          |           |
| 5-70. |          |      |        |           |          |           |
+-------+----------+------+--------+-----------+----------+-----------+

## Osteonecrosis of the jaw (ONJ)

Jaw bones are unique in that they are the only bones in the body that
are constantly exposed to the external environment due to the presence
of teeth. Additionally, the jaw bones are subject to the risk of
repeated trauma and injury from dental procedures such as routine
cleaning or other necessary medical interventions. Thus, the jaw bones
are more susceptible to infection, and are in need of mechanisms to deal
with the chronic mechanical or infectious insults.

Osteonecrosis of the jaw (ONJ) has been reported since the 19th century,
though the number of such reports as been small.

One of the variants of ONJ is known as neuralgia-inducing cavitational
necrosis (NICO), which is defined as a chronic neurogenic pain syndrome
caused by alveolar bone necrosis and the formation of intrabony cavities
of significant size (Bouquot 1992a, Bouquot 1992b, Bouquot 1995, Bouquot
1997, Freedman 1998, Bouquot 2000, Shankland 2002). While there is still
debate on whether "NICO" represents a true disease entity (Zuniga 2000,
Bouquot 2003), histopathological features of NICO clearly indicate
presence of bone necrosis, suggesting ischemia as a possible pathogenic
mechanism (Bouquot 1995, Brontons 2003). It is likely that some reports
of osteomyelitis, particularly when chronic and persistent in nature,
are in fact cases of osteonecrosis, which may occur as a result of
infection (osteomyelitis) of the jaw bone, or present as osteomyelitis
due to infection of the dead bone.

Unlike ON of other sites, a clear set of diagnostic criteria is lacking
for ONJ. The disease may present clinically as "facial pain", jaw pain,
chronic osteomyelitis of the jaw, exposed jaw bone, cavitary alveolar
osteopathy, sequestration of alveolar bone, and a number of other signs
and symptoms (Brontons 2003). An example of the current diagnostic
complexity and the confusion regarding clear criteria of diagnosis for
ONJ is a recent case report that refers to cases of "osteomyelitis" in
the title, but these cases are in fact ONJ when one reads the
description of the cases (Lugassy 2004).

The pathogenesis of ONJ is not understood. It is possible that some of
the risk factors and the pathogenic pathways for ON at other sites may
also contribute to the development of ONJ. Shroyer et al (1991) reported
and reviewed cases of osteomyelitis of the mandible in patients with
sickle cell disease, and Kavadia-Tsatala et al (2004) reported 6 cases
of mandibular bone infarcts in 42 patients with sickle cell
hemoglobinopathy which is known to cause vasoocclusive crises. Moreover,
Glueck (1997a), Glueck (1997b) reported presence of coagulopathy in 73%
of 124 ONJ patients, manifested as either thrombophilia or
hypofibrinolysis or both. Shankland (2002) reviewed 500 cases of ONJ and
found evidence of impaired blood flow in the jaw bone or teeth in \>95%
of these patients. Moreover, blood flow to the jaw bone was shown to be
reduced by chronic osteomyelitis (Wannfors and Gazelius 1991). These
findings strongly implicate impaired circulation in the pathogenesis of
ONJ.

An infectious cause of ONJ has been suggested in patients suffering from
trigeminal herpes zoster which can induce vasculitis leading to ischemia
(Schwartz 1989, Arikawa 2004). ONJ was also reported in patients with
HIV infection (Schwartz 1989).

## ONJ in cancer patients

Prior to 2003, ONJ in cancer patients was described in two case reports
(Schwartz 1982; Sung 2002). Schwartz (1982) reported two cases of ONJ in
patients with head and neck cancer that occurred after chemotherapy. One
of the patients had mucosal infection prior to bone infection
(osteomyelitis) and ONJ, and the other had dentures producing
irritation. The potential role for chemotherapy in ONJ was also
suggested by Sung et al (2002) who reported ONJ in patients with acute
myelogenous leukemia (AML) treated with chemotherapy without steroids.
While cancer and chemotherapy are noted as risk factors for ON (Appendix
1), the background incidence of ONJ in cancer patients and the general
population is unknown.

Osteoradionecrosis (ORN), a specific form of ONJ which occurs after
radiation to patients with head and neck cancer, has a reported
incidence varying between 0.4 -- 56% (Jerecaek-Fossa and Orecchia 2002).
The incidence has decreased due to preventive oral hygiene measures and
careful dental evaluation before and after irradiation. A recent study
reported an ORN incidence of 8.2% in these patients (Reuther et al,
2003). Besides radiation itself, the risk factors for ORN are similar to
those described for ON in cancer patients, and the patients remain at
indefinite risk of ORN after radiation (Jerecaek-Fossa and Orecchia
2002). The mechanism for ORN involves radiation-induced damage to
vasculature and bone tissues, and like ON in general, ischemia is
hypothesized to be the ultimate immediate cause of death of bony tissue.
The study of Bras et al (1990) showed obliteration by radiotherapy of
the inferior alveolar artery that supplies portions of the mandible,
providing strong evidence for ischemia as a mechanism of bone necrosis
in ORN.

ONJ in cancer patients treated with a bisphosphonate was first reported
by Marx (2003). Several reports have been published subsequently
describing ONJ in patients receiving bisphosphonates. These reports are
summarized in Section 4.

In summary, multiple risk factors and medical conditions are associated
with ON, which occurs more frequently in cancer patients, presumably due
to the underlying diseases and their therapy (Appendix 2). The
pathogenesis of ON is not clearly understood, but impaired blood supply
to the bone may be the final common pathway prior to death of bone
tissues. ON causes significant morbidity and disability, and necessary
measures should be taken to prevent or reduce the occurrence of ON in
patients who have the known risk factors mentioned above. Additionally,
ONJ is a specific form of ON that has specific local risk factors
because of the unique properties of the jaw bone, and risk factors known
to cause ON in general may also come into play in the pathogenesis of
ONJ.

## Preclinical data on bisphosphonates and osteonecrosis

The primary pharmacologic action of bisphosphonates such as pamidronate
and zoledronic acid is to reduce osteoclastic bone resorption by
inhibiting a key intracellular enzyme for lipid metabolism (farnesyl
diphosphate synthase) in the osteoclast, which subsequently induces
apoptosis (Rogers 2003). As bisphosphonates are highly charged,
hydrophilic compounds that rapidly bind to bone, only endocytic cells in
bone such as osteoclasts are normally exposed to pharmacologically
active concentrations of drug. Osteonecrosis of the jaws or any other
skeletal site was not observed in any of the in vivo profiling studies
with zoledronic acid and pamidronate, nor have there been any reports of
it in the preclinical literature for other bisphosphonates. In two rat
models of aseptic osteonecrosis of the femoral head, zoledronic acid has
been shown to exert a beneficial effect and thus was proposed as a
clinical therapy for this condition (Little 2003a, Little 2003b).
Recently there have been several publications on inhibition of
angiogenesis in soft tissue and bone tumors by bisphosphonates,
including pamidronate and zoledronic acid (Wood 2002, Fournier 2002,
Croucher 2003, Fournier 2003, Giraudo 2004) but there have been no
reports of a corresponding anti-angiogenic effect in normal bone that is
being newly formed, remodeled or undergoing fracture repair -- processes
that are all dependent on angiogenesis (Hunziker et al 2000).
Bisphosphonates have been extensively studied in animals models of
periodontal disease, and, despite dental interventions such as tooth
ligation, osteonecrosis of the jaws has not been reported in association
with bisphosphonate treatment (Brunsvold 1992, Weinreb 1994, Reddy 1995,
Shoji 1995, O\'uchi 1998; Shibutani 2001).

A comprehensive preclinical safety assessment has been performed for
pamidronate and zoledronic that included a wide range of oral and
parenteral toxicology studies in multiple animal species at doses
comparable to and at many multiples of those typically administered to
the oncology patient (90 mg pamidronate, 4 mg zoledronic acid). No
findings comparable to ONJ were observed in the bone specimens collected
and evaluated from any of the animal studies. Moreover, a careful search
of the literature did not reveal any known association between
bisphosphonate administration and ONJ in animals. Animal experiments to
study the possible role of bisphosphonates (including pamidronate and
zoledronic acid) in the etiology and pathogenesis of ONJ were considerd.
However, it was concluded that the design and conduct of such studies
would be inordinately complex considering its multifactorial etiology,
and traumatic (e.g. tooth evulsion studies in the canine) yielding what
could at best be considered equivocal results.

# Reported cases of osteonecrosis of the jaw

## Cases of ONJ reported in the literature

ONJ in cancer patients treated with IV bisphosphonates was first
reported by Marx et al (2003) in the September 2003 issue of the Journal
of Oral and Maxillofacial Surgery. A collection of case reports was
published by Ruggiero et al (2004) in the same journal in 2004. The
sixty three (63) patients described in this paper had been treated with
either IV or in a few cases with oral bisphosphonates.

During the latter half of 2004, there was some discussion of ONJ, as
summarized in Table 4-1.

###### Table 4-5 References 2004 {#table-4-5-references-2004 .unnumbered}

+----------------+--------+-------------------------+-----------------+
| **Author**     | **No   | **Journal**             | **Methodology** |
|                | of ONJ |                         |                 |
|                | Pts    |                         |                 |
|                | Repo   |                         |                 |
|                | rted** |                         |                 |
+----------------+--------+-------------------------+-----------------+
| (de Almeida,   | 5      | Rev Bras Oncologia      | Case Report     |
| de Araujo and  |        | Clinica (Brazil)        |                 |
| Pires 2004)    |        |                         |                 |
+----------------+--------+-------------------------+-----------------+
| (Bagan et al   | 10     | J Oral Pathol Med       | Case Report,    |
| 2004)          |        |                         | Manuscript      |
+----------------+--------+-------------------------+-----------------+
| (Curreli et al | 1      | MASCC/ISOO Symposium\*  | Case Report,    |
| 2004)          |        |                         |                 |
|                |        |                         | Abstract        |
+----------------+--------+-------------------------+-----------------+
| (Durie et al   | 62     | Blood                   | Abstract,       |
| 2004)          |        |                         |                 |
|                |        |                         | Anonymous web   |
|                |        |                         | based survey    |
+----------------+--------+-------------------------+-----------------+
| (Kut et al     | No     | Blood                   | Abstract        |
| 2004)          | cases  |                         |                 |
|                | found  |                         |                 |
+----------------+--------+-------------------------+-----------------+
| (Lugassy et al | 3      | The American Journal of | Case Report,    |
| 2004)          |        | Medicine                |                 |
|                |        |                         | Letter to the   |
|                |        |                         | Editor          |
+----------------+--------+-------------------------+-----------------+
| (McMahon et al | No     | Journal of Oral and     | Letter to the   |
| 2004)          | cases  | Maxillofacial Surgery   | Editor          |
|                | dis    |                         |                 |
|                | cussed |                         |                 |
+----------------+--------+-------------------------+-----------------+
| (Schuster and  | 2      | Blood                   | Case Reports,   |
| Dymek 2004)    |        |                         |                 |
|                |        |                         | Abstract        |
+----------------+--------+-------------------------+-----------------+
| (Thakkar et al | 14     | Blood                   | Case Reports,   |
| 2004)          |        |                         |                 |
|                |        |                         | Abstract        |
+----------------+--------+-------------------------+-----------------+
| (Van Poznack   | 6      | San Antonio Breast      | Clinical        |
| et al 2004)    |        | Cancer Symposium        | Database        |
|                |        |                         | Review,         |
|                |        |                         |                 |
|                |        |                         | Abstract        |
+----------------+--------+-------------------------+-----------------+

Though these various reports provide information for additional
consideration, they are subject to a variety of limitations. For
example, there is no standard definition of ONJ applied across these
reports. ONJ was used to describe a variety of diagnoses and
pathologies, including osteomyelitis, osteonecrosis, suspicious findings
for osteonecrosis, ischemic bone disease, cavitational osteonecrosis,
and bone marrow edema among others. Further, the amount of clinical data
upon which the case reports are based is inconsistent. The Durie
web-based survey is based on data collected from anonymous respondents.
At the December 2004 ASH Meeting Durie et al (2004) presented findings
from their web-based survey of 1,203 anonymous respondents. Respondents
were recruited using the International Myeloma Foundation (IMF) email
lists/website plus "ACOR" myeloma and breast listservs (e-mail), Nexcura
(e-mail) and Y-Me National Breast Cancer Organization (web-based). The
information was supplied anonymously by the respondents and therefore
could not be validated against medical records. The bias associated with
this survey methodology may be significant and has the potential to
substantially affect the generalization of the study conclusions,
including that ONJ occurs earlier with Zometa than with Aredia use, and
that other therapies do not significantly increase the likelihood of
ONJ.

In addition to bisphosphonates, the publications in Table 4-1 lists
other factors that could contribute to the risk of ONJ, including
chemotherapy, corticosteroids, thalidomide, surgical procedures in the
oral cavity, transplantation, immune suppression, and
inflammation/infection. Many of the cases reported were noted following
tooth extraction.

## Cases of ONJ reported to Novartis

ONJ in patients treated with intravenous pamidronate (Aredia) or
zoledronic acid (Zometa) was first reported to Novartis in December 2002
(a spontaneous report).

Table 4-2 shows cases of osteonecrosis of the jaw in patients treated
with Zometa and/or Aredia reported to the Novartis Clinical Safety and
Epidemiology Department as of December 7, 2004. The current tally of the
type of reports is as follows: 531 spontaneous reports and 79 literature
cases for a total of 610 reports. It is estimated that up to November
2004 approximately 2.8 million patients have been treated worldwide with
Aredia and/or Zometa.

###### Table 4-6 Reports of ONJ (including reportable cases from the literature) associated with the use of Zometa/Aredia (as of December 7, 2004) {#table-4-6-reports-of-onj-including-reportable-cases-from-the-literature-associated-with-the-use-of-zometaaredia-as-of-december-7-2004 .unnumbered}

+-----------------+-------------------------------+---------+---+---------+
|                 | **Cases under Aredia and/or   | **N**   |   | **%**   |
|                 | Zometa**                      |         |   |         |
+-----------------+-------------------------------+---------+---+---------+
|                 |                               | **610** |   | **100   |
|                 |                               |         |   | %**     |
+-----------------+-------------------------------+---------+---+---------+
| Agent (suspect  | Zometa only^\*^               | 374     |   | 61.3%   |
| drug)           |                               |         |   |         |
|                 | Aredia only\*\*\*\*           | 120     |   | 19.7%   |
|                 |                               |         |   |         |
|                 | Both\*\*                      | 116     |   | 19.0%   |
+-----------------+-------------------------------+---------+---+---------+
| Countries       | US                            | 440     |   | 72.1%   |
|                 |                               |         |   |         |
|                 | Non-US                        | 170     |   | 27.9%   |
+-----------------+-------------------------------+---------+---+---------+
|                 |                               |         |   |         |
+-----------------+-------------------------------+---------+---+---------+
| Indication      | Multiple Myeloma              | 218     |   | 35.7%   |
|                 |                               |         |   |         |
|                 | Breast                        | 125     |   | 20.5%   |
|                 |                               |         |   |         |
|                 | Other                         | 267     |   | 43.8%   |
+-----------------+-------------------------------+---------+---+---------+
| Age^\*\*\*^     | Range                         | 27 --   |   |         |
|                 |                               | 93      |   |         |
|                 | Mean                          | years   |   |         |
|                 |                               |         |   |         |
|                 |                               | 62.6    |   |         |
|                 |                               | (f      |   |         |
|                 |                               | emales) |   |         |
|                 |                               |         |   |         |
|                 |                               | 66.4    |   |         |
|                 |                               | (males) |   |         |
+-----------------+-------------------------------+---------+---+---------+
| Gender          | Female                        | 340     | 5 |         |
|                 |                               |         | 6 |         |
|                 | Male\                         | 231\    | % |         |
|                 | Unknown                       | 39      |   |         |
|                 |                               |         | 3 |         |
|                 |                               |         | 9 |         |
|                 |                               |         | % |         |
|                 |                               |         | \ |         |
|                 |                               |         | 6 |         |
|                 |                               |         | . |         |
|                 |                               |         | 4 |         |
|                 |                               |         | % |         |
+-----------------+-------------------------------+---------+---+---------+
| \* 126 of these |                               |         |   |         |
| 374 cases had   |                               |         |   |         |
| received prior  |                               |         |   |         |
| treatment with  |                               |         |   |         |
| Aredia          |                               |         |   |         |
|                 |                               |         |   |         |
| \*\* The two    |                               |         |   |         |
| drugs were      |                               |         |   |         |
| given most      |                               |         |   |         |
| frequently      |                               |         |   |         |
| sequentially,   |                               |         |   |         |
| but in a few    |                               |         |   |         |
| cases the       |                               |         |   |         |
| treatments were |                               |         |   |         |
| switched back   |                               |         |   |         |
| and forth for   |                               |         |   |         |
| unknown         |                               |         |   |         |
| reasons.        |                               |         |   |         |
|                 |                               |         |   |         |
| \*\*\* Age not  |                               |         |   |         |
| reported in 142 |                               |         |   |         |
| cases           |                               |         |   |         |
|                 |                               |         |   |         |
| \*\*\*\* One    |                               |         |   |         |
| case received   |                               |         |   |         |
| prior treatment |                               |         |   |         |
| with Zometa     |                               |         |   |         |
+-----------------+-------------------------------+---------+---+---------+

In 303 (50%) of the cases potential triggering events like dental
surgery, local trauma, tooth extraction or dental infection preceded the
diagnosis of ONJ. In 450 (74%) of the reports the patients had at least
one of the risk factors for osteonecrosis.

Spontaneous report databases are known to be affected by multiple
biases. In addition, the ONJ reports received are deficient with respect
to medical and dental history, and concomitant medication information.
Even after aggressive follow-up efforts by the sponsor, many cases can
be considered to be only scantly described. The frequent lack of
important case details leads to serious limitations to the analyses and
interpretation of the findings from the spontaneous report database.
However, the majority of cases for which some clinical details are
available include significant risk factors for ON. Novartis is fully
committed to continue the investigation of these cases.

Further epidemiologic data on these cases, including concomitant risk
factors and duration of exposure to bisphosphonate treatment, are given
in the Aredia and Zometa Comprehensive Medical safety Evaluation:
Osteonecrosis of the Maxillofacial Area -- December 2004 Overview \[see
(Appendix 3)\].

Cases of osteonecrosis of the jaw (ONJ) in clinical studies

Since the specific term "osteonecrosis of the jaw" (ONJ) does not exist
in the MedDRA dictionary (version 6.1), the clinical trial database for
Zometa and Aredia was screened using 18 MedDRA terms that may identify
cases related to ONJ. As of January 2005, we have searched 25 completed
Zometa bone metastases studies (pivotal and non-pivotal), 3 pivotal
Aredia bone metastases studies and 3 pivotal Zometa hypercalcemia trials
involving more than 8,000 patients. Table 4-3 summarizes these studies,
and details of these trials are presented in Appendix 4. Additional
searches are being conducted for ongoing oncology studies of Zometa
where databases are available.

The terms used in the search followed MedDRA 6.1. and include:

Bone debridment jaw lesion excision

Jaw operation mandibulectomy

Maxillofacial operation oral surgery

Aseptic necrosis bone bone infarction

Necrosis osteomyelitis acute

Osteomyelitis chronic osteomyelitis drainage

Osteomyelitis osteonecrosis

Primary sequestrum secondary sequestrum

Sequestrectomy tertiary sequestrum

###### Table 4-7 Completed Zometa and Aredia studies included in the search for terms related to ONJ using MedDRA terms {#table-4-7-completed-zometa-and-aredia-studies-included-in-the-search-for-terms-related-to-onj-using-meddra-terms .unnumbered}

+------------------------------+--------------------+-----------------+
| **Pivotal trials (Zometa +   | **Treatment        | **No. of        |
| Aredia)**                    | Group**            | patients**      |
+------------------------------+--------------------+-----------------+
| **Bone metastases Zometa**   |                    |                 |
+------------------------------+--------------------+-----------------+
| \[CZOL4460007+E\]            | Zometa             | 183             |
+------------------------------+--------------------+-----------------+
|                              | Zometa/Aredia      | 30              |
+------------------------------+--------------------+-----------------+
|                              | Aredia             | 75              |
+------------------------------+--------------------+-----------------+
| \[CZOL4460010+E\]            | Zometa             | 1,090           |
+------------------------------+--------------------+-----------------+
|                              | Aredia             | 558             |
+------------------------------+--------------------+-----------------+
| \[CZOL4460011+E\]            | Zometa             | 523             |
+------------------------------+--------------------+-----------------+
|                              | Placebo            | 250             |
+------------------------------+--------------------+-----------------+
| \[CZOL4460039+E\]            | Zometa             | 435             |
+------------------------------+--------------------+-----------------+
|                              | Placebo            | 208             |
+------------------------------+--------------------+-----------------+
| \[CZOL4460704\]              | Zometa             | 204             |
+------------------------------+--------------------+-----------------+
|                              | Placebo            | 201             |
+------------------------------+--------------------+-----------------+
| **Subtotal**                 |                    | **3757**        |
+------------------------------+--------------------+-----------------+
| **Bone metastases Aredia**   |                    |                 |
+------------------------------+--------------------+-----------------+
| \[CARD233AP12\]              | Aredia             | 203             |
+------------------------------+--------------------+-----------------+
|                              | Placebo            | 189             |
+------------------------------+--------------------+-----------------+
| \[CARD233AP18                | Aredia             | 182             |
+------------------------------+--------------------+-----------------+
|                              | Placebo            | 189             |
+------------------------------+--------------------+-----------------+
| CARD233AP19\]                | Aredia             | 185             |
+------------------------------+--------------------+-----------------+
|                              | Placebo            | 197             |
+------------------------------+--------------------+-----------------+
| **Subtotal**                 |                    | **1145**        |
+------------------------------+--------------------+-----------------+
| **Hypercalcemia Zometa**     |                    |                 |
+------------------------------+--------------------+-----------------+
| \[CHJC1\]                    | Zometa             | 33              |
+------------------------------+--------------------+-----------------+
| \[CZOL446036\]               | Zometa             | 94              |
+------------------------------+--------------------+-----------------+
|                              | Aredia             | 50              |
+------------------------------+--------------------+-----------------+
| \[CZOL446037\]               | Zometa             | 87              |
+------------------------------+--------------------+-----------------+
|                              | Aredia             | 51              |
+------------------------------+--------------------+-----------------+
| **Subtotal**                 |                    | **315**         |
+------------------------------+--------------------+-----------------+
| **Total for Pivotal          |                    | **5217**        |
| Studies**                    |                    |                 |
+------------------------------+--------------------+-----------------+
|                              |                    |                 |
+------------------------------+--------------------+-----------------+
| **Non-Pivotal trials         | **Treatment        | **No. of        |
| (Zometa)**                   | Group**            | patients**      |
|                              |                    |                 |
| **Bone metastases**          |                    |                 |
+------------------------------+--------------------+-----------------+
| **Phase I-III**              |                    |                 |
+------------------------------+--------------------+-----------------+
| \[CZOL4460001\]^1)^          | Zometa             | 16              |
+------------------------------+--------------------+-----------------+
| \[CZOL4460002\]^1)^          | Zometa             | 140             |
+------------------------------+--------------------+-----------------+
|                              | Placebo            | 35              |
+------------------------------+--------------------+-----------------+
| \[CZOL4460003+E\]            | Zometa             | 59              |
+------------------------------+--------------------+-----------------+
| \[CZOL4460035+E\]            | Zometa             | 42              |
+------------------------------+--------------------+-----------------+
| \[CZOL4460503+E\]            | Zometa             | 36              |
+------------------------------+--------------------+-----------------+
| \[CZOL4460506+E\]            | Zometa             | 19              |
+------------------------------+--------------------+-----------------+
| \[CZOL4460510\]              | Zometa             | 20              |
+------------------------------+--------------------+-----------------+
| \[CZOL4460705\]              | Zometa             | 55              |
+------------------------------+--------------------+-----------------+
|                              | Placebo            | 51              |
+------------------------------+--------------------+-----------------+
| \[CZOL446IA03\]              | Zometa             | 115             |
+------------------------------+--------------------+-----------------+
|                              | Aredia             | 125             |
+------------------------------+--------------------+-----------------+
| **Subtotal**                 |                    | **713**         |
+------------------------------+--------------------+-----------------+
| **Phase IV**                 |                    |                 |
+------------------------------+--------------------+-----------------+
| \[CZOL446EDE02\]             | Zometa             | 604             |
+------------------------------+--------------------+-----------------+
| \[CZOL446EIT01\]             | Zometa             | 312             |
+------------------------------+--------------------+-----------------+
| \[CZOL446EAU05\]             | Zometa             | 184             |
+------------------------------+--------------------+-----------------+
| \[CZOL446EAU07\]             | Zometa             | 11              |
+------------------------------+--------------------+-----------------+
| \[CZOL446GAU09\]             | Zometa             | 2               |
+------------------------------+--------------------+-----------------+
| \[CZOL446EGB01\]             | Zometa             | 101             |
+------------------------------+--------------------+-----------------+
| \[CZOL446EIN01\]             | Zometa             | 73              |
+------------------------------+--------------------+-----------------+
| \[CZOL446EPH01\]             | Zometa             | 70              |
+------------------------------+--------------------+-----------------+
| \[CZOL446GFR02\]             | Zometa             | 102             |
+------------------------------+--------------------+-----------------+
| \[CZOL446EUS16\]             | Zometa             | 638             |
+------------------------------+--------------------+-----------------+
| \[CZOL446EUS24\]             | Zometa             | 257             |
+------------------------------+--------------------+-----------------+
| **Subtotal**                 |                    | **2354**        |
+------------------------------+--------------------+-----------------+
|                              |                    |                 |
+------------------------------+--------------------+-----------------+
| **TOTAL**                    |                    | **8,284**       |
+------------------------------+--------------------+-----------------+

### Completed studies

The screen using the 18 MedDRA terms produced 24 matches. After medical
review, 6 cases were determined to be consistent with a potential
diagnosis of ONJ. Four of these were reported as osteomyelitis with jaw
as the affected site. Although 3 of the 4 osteomyelitis cases did not
report exposed or necrotic bone and thus cannot be definitively
diagnosed as ONJ, we included them because of the lack of a clear case
definition for ONJ and the fact that known ONJ cases have occasionally
been reported as osteomyelitis (see Section 3).

The 6 cases of ONJ or osteomyelitis of the jaw (OMJ) were all found in
the randomized pivotal studies (total of 11 trials, see Table 4-4). None
of these were reported as serious or related to the study drug as
assessed by the investigator. A summary of these 6 cases is presented in
Table 4-5. Details of the 6 cases are summarized in Appendix 4.

The screening also identified 2 cases of osteomyelitis or osteonecrosis
with unknown location, and involvement of the jaw has not been confirmed
at this time (Appendix 4).

In addition, one case of osteoradionecrosis was identified in the Zometa
8/4 mg arm, and radiation injury was clearly described in this patient
(Appendix 4).

###### Table 4-8 Summary of the ONJ cases in randomized pivotal clinical trials {#table-4-8-summary-of-the-onj-cases-in-randomized-pivotal-clinical-trials .unnumbered}

+--------------+------------+---------+--------------+----------------+
| *            | **\# of    | **\# of | **\# of      | **Tumor type** |
| *Treatment** | pa         | ONJ**   | Infusions**  |                |
|              | tients\*** |         |              |                |
+--------------+------------+---------+--------------+----------------+
| Zol 4 mg     | 1168       | 1       | 28           | MM             |
+--------------+------------+---------+--------------+----------------+
| Zol 8 mg     | 219        | 1       | 1^1)^        | Head&Neck      |
+--------------+------------+---------+--------------+----------------+
| Zol 8/4 mg   | 1227       | 2       | 20^2)^       | PC             |
|              |            |         |              |                |
|              |            |         | 17^3)^       | MM             |
+--------------+------------+---------+--------------+----------------+
| Aredia 90 mg | 1334       | 2       | 14           | MM             |
|              |            |         |              |                |
|              |            |         | 28^4)^       | MM             |
+--------------+------------+---------+--------------+----------------+
| Placebo      | 1234       | 0       |              |                |
+--------------+------------+---------+--------------+----------------+
| \* Patient   |            |         |              |                |
| number of    |            |         |              |                |
| study        |            |         |              |                |
| CHJC1(n=33)  |            |         |              |                |
| not included |            |         |              |                |
| as dose      |            |         |              |                |
| regimen      |            |         |              |                |
| cannot be    |            |         |              |                |
| attributed   |            |         |              |                |
| to the       |            |         |              |                |
| categories   |            |         |              |                |
| presented in |            |         |              |                |
| this table   |            |         |              |                |
|              |            |         |              |                |
| ^1)^HCM      |            |         |              |                |
| study        |            |         |              |                |
|              |            |         |              |                |
| ^2)^The      |            |         |              |                |
| patient      |            |         |              |                |
| received 7   |            |         |              |                |
| infusions of |            |         |              |                |
| Zometa 8 mg  |            |         |              |                |
| before       |            |         |              |                |
| switching to |            |         |              |                |
| Zometa 4 mg  |            |         |              |                |
| 13           |            |         |              |                |
| infusions)   |            |         |              |                |
|              |            |         |              |                |
| ^3)^The      |            |         |              |                |
| patient      |            |         |              |                |
| received 10  |            |         |              |                |
| infusions of |            |         |              |                |
| Zometa 4 mg  |            |         |              |                |
| before       |            |         |              |                |
| switching to |            |         |              |                |
| Zometa 8 mg  |            |         |              |                |
| (7           |            |         |              |                |
| infusions)   |            |         |              |                |
|              |            |         |              |                |
| ^4)^The      |            |         |              |                |
| patient      |            |         |              |                |
| received 10  |            |         |              |                |
| infusions of |            |         |              |                |
| Zometa 0.4   |            |         |              |                |
| mg before    |            |         |              |                |
| switching to |            |         |              |                |
| Aredia (18   |            |         |              |                |
| infusions)   |            |         |              |                |
+--------------+------------+---------+--------------+----------------+

As shown in Table 4-4, ONJ was uncommon in randomized pivotal trials,
with 6 cases out of 3,981 patients treated with either Zometa or Aredia
(2,647 Zometa patients, and 1,334 Aredia patients). However, due to the
small number of ONJ cases in pivotal clinical trials, an incidence by
treatment group cannot be reliably calculated. Nevertheless, 1 case of
ONJ was found in the 1,168 patients receiving 4 mg Zometa, and 2 cases
of ONJ were observed in 1,334 patients receiving 90 mg Aredia, which are
the dosage of Zometa and Aredia approved for clinical use. No cases of
ONJ were found in the 1,234 placebo patients in these studies.

Review of the 6 ONJ or OMJ cases revealed multiple risk factors. Five
patients had chemotherapy, and 4 of them also had concomitant
corticosteroids in their treatment regimen. Various oral infections were
present in 4 patients, one patient had tooth extraction and in one
patient poor dentition was reported (Table 4-6, for details see Appendix
4).

ONJ was not found in non-pivotal or post-marketing studies that have
been completed as of January 2005 (total of 20 trials, 3,067 patients,
see Appendix 4).

###### Table 4-9 ONJ/OMJ cases reported in pivotal bone metastases and hypercalcemia trials: possible risk factors {#table-4-9-onjomj-cases-reported-in-pivotal-bone-metastases-and-hypercalcemia-trials-possible-risk-factors .unnumbered}

+--------+--------+-------+-------+-------+--------+------------------+
| *      | *      | **D   | *     | *     | **No.  | **Possible risk  |
| *Study | *Tumor | iagno | *Date | *Date | in     | factors**        |
| No.**  | type** | sis** | of    | of    | fusion |                  |
|        |        |       | 1^st^ | ON    | s^)^** |                  |
|        |        |       | infus | J/OMJ |        |                  |
|        |        |       | ion** | d     |        |                  |
|        |        |       |       | iagno |        |                  |
|        |        |       |       | sis** |        |                  |
+========+========+=======+=======+=======+========+==================+
| \[CZ   | Mu     | ONJ   | 4     | Mar99 | 28     | Chemotherapy;    |
| OL446G | ltiple |       | Nov96 |       |        | cortico­steroids; |
|        | m      |       |       |       |        | candidal         |
| 0007\] | yeloma |       |       |       |        | infection; tooth |
|        |        |       |       |       |        | abscess          |
+--------+--------+-------+-------+-------+--------+------------------+
|        | Mu     | OMJ   | 24    | 9     | 17     | Chemotherapy;    |
|        | ltiple |       | Oct96 | Apr98 |        | cortico­steroids; |
|        | m      |       |       |       |        | radiolucency at  |
|        | yeloma |       |       |       |        | mandible seen on |
|        |        |       |       |       |        | a radiograph of  |
|        |        |       |       |       |        | the skull; jaw   |
|        |        |       |       |       |        | infection;       |
|        |        |       |       |       |        | osteoarthritis   |
+--------+--------+-------+-------+-------+--------+------------------+
| \[CZ   | Mu     | OMJ   | 10    | 5     | 28     | Chemotherapy;    |
| OL446G | ltiple |       | May99 | Mar01 |        | cortico­steroids; |
|        | m      |       |       |       |        | ulcer mouth;     |
| 0010\] | yeloma |       |       |       |        | cyst under chin; |
|        |        |       |       |       |        | infection of the |
|        |        |       |       |       |        | gum and teeth    |
+--------+--------+-------+-------+-------+--------+------------------+
| \[CZ   | Pr     | OMJ   | 29    | 26    | 20     | Dental abscess,  |
| OL446G | ostate |       | Dec99 | Mar02 |        | tooth            |
|        | cancer |       |       |       |        | extraction; oral |
| 0704\] |        |       |       |       |        | fistula;         |
|        |        |       |       |       |        | arthritis;       |
|        |        |       |       |       |        | hormone therapy  |
+--------+--------+-------+-------+-------+--------+------------------+
| \[CARD | Mu     | OMJ   | 20    | 21    | 14     | Chemotherapy;    |
|        | ltiple |       | Aug91 | Oct92 |        | cortico­steroids; |
| 233    | m      |       |       |       |        | dentition poor;  |
| AP12\] | yeloma |       |       |       |        | denuded bone     |
|        |        |       |       |       |        | (mandible)       |
+--------+--------+-------+-------+-------+--------+------------------+
| \[C    | SSC    | ONJ   | 16    | 28    | 1      | Chemotherapy     |
| ZOL446 | Hea    |       | Jul99 | Jul99 |        |                  |
|        | d&Neck |       |       |       |        |                  |
| 0037\] |        |       |       |       |        |                  |
+--------+--------+-------+-------+-------+--------+------------------+

### Ongoing studies

Three reports of serious adverse events consistent with findings
suspicious of ONJ have been reported in ongoing Zometa oncology clinical
trials involving more than 8,000 patients. Two of these serious adverse
events were considered as not related to the study drug by the
investigator. We have also received an additional report of ONJ that is
considered non-serious by the investigator.

One of the patients had preexisting osteomyelitis of the jaw. Two
patients had received chemotherapy and 1 corticosteroids in medical
history or as current condition.

We do not have any currently ongoing studies with Aredia.

These cases are summarized in Table 4-6 (for details see Appendix 4).

###### Table 4-10 ONJ cases reported in ongoing Zometa bone metastases studies {#table-4-10-onj-cases-reported-in-ongoing-zometa-bone-metastases-studies .unnumbered}

+---------+-------+--------+-------+---------+--------+---------------+
| **Table | **    | *      | *     | **Date  | **No.  | **Possible    |
| .**     | Tumor | *Diagn | *Date | of      | infus  | risk          |
|         | T     | osis** | of    | ONJ/OMJ | ions** | factors^2)^** |
|         | ype** |        | 1^st^ | diag    |        |               |
|         |       |        | infus | nosis** |        |               |
|         |       |        | ion** |         |        |               |
+=========+=======+========+=======+=========+========+===============+
| \[C     | B     | ONJ    | 26    | Oc      | Max. 4 | Chemotherapy; |
| ZOL446G | reast |        | Jan04 | t04^1)^ |        | cor           |
|         | c     |        |       |         |        | ticosteroids; |
| 2408\]  | ancer |        |       |         |        | gingival      |
|         |       |        |       |         |        | infection;    |
|         |       |        |       |         |        | dental        |
|         |       |        |       |         |        | extraction    |
+---------+-------+--------+-------+---------+--------+---------------+
| \[C     | Pro   | OMJ    | 25    | Already | Max. 9 | Preexisting   |
| ZOL446E | state |        | Feb03 | present |        | osteomyelitis |
|         | c     |        |       | at      |        | of the jaw    |
| DE07\]  | ancer |        |       | study   |        |               |
|         |       |        |       | en      |        |               |
|         |       |        |       | try^2)^ |        |               |
+---------+-------+--------+-------+---------+--------+---------------+
| \[C     | B     | ONJ    | 25    | After   | Max. 4 | Chemotherapy; |
| ZOL446E | reast |        | Jul03 |         |        | chronic       |
|         | c     |        |       | 6Jan    |        | gingivitis    |
| D       | ancer |        |       | 04^3)^  |        |               |
| EKR02\] |       |        |       |         |        |               |
+---------+-------+--------+-------+---------+--------+---------------+
| \[C     | Mul   | ONJ    | ?     | ?       | ?      | ?             |
| ZOL446E | tiple |        |       |         |        |               |
|         | my    |        |       |         |        |               |
| DE01\]  | eloma |        |       |         |        |               |
+---------+-------+--------+-------+---------+--------+---------------+
| ^1)^    |       |        |       |         |        |               |
| Patient |       |        |       |         |        |               |
| r       |       |        |       |         |        |               |
| eceived |       |        |       |         |        |               |
| tooth   |       |        |       |         |        |               |
| ext     |       |        |       |         |        |               |
| raction |       |        |       |         |        |               |
| due to  |       |        |       |         |        |               |
| g       |       |        |       |         |        |               |
| ingival |       |        |       |         |        |               |
| in      |       |        |       |         |        |               |
| fection |       |        |       |         |        |               |
| on      |       |        |       |         |        |               |
| F       |       |        |       |         |        |               |
| ebruary |       |        |       |         |        |               |
| 16,     |       |        |       |         |        |               |
| 2004.   |       |        |       |         |        |               |
| Tooth   |       |        |       |         |        |               |
| ext     |       |        |       |         |        |               |
| raction |       |        |       |         |        |               |
| site    |       |        |       |         |        |               |
| did not |       |        |       |         |        |               |
| heal.   |       |        |       |         |        |               |
| Patient |       |        |       |         |        |               |
| was     |       |        |       |         |        |               |
| treated |       |        |       |         |        |               |
| by      |       |        |       |         |        |               |
| deb     |       |        |       |         |        |               |
| ridment |       |        |       |         |        |               |
| of the  |       |        |       |         |        |               |
| jaw     |       |        |       |         |        |               |
| bone    |       |        |       |         |        |               |
| and     |       |        |       |         |        |               |
| cu      |       |        |       |         |        |               |
| rettage |       |        |       |         |        |               |
| of      |       |        |       |         |        |               |
| n       |       |        |       |         |        |               |
| ecrotic |       |        |       |         |        |               |
| bone.   |       |        |       |         |        |               |
|         |       |        |       |         |        |               |
| ^2)^    |       |        |       |         |        |               |
| Patient |       |        |       |         |        |               |
| hospi   |       |        |       |         |        |               |
| talized |       |        |       |         |        |               |
| on      |       |        |       |         |        |               |
| January |       |        |       |         |        |               |
| 6, 2004 |       |        |       |         |        |               |
| to      |       |        |       |         |        |               |
| receive |       |        |       |         |        |               |
| local   |       |        |       |         |        |               |
| tr      |       |        |       |         |        |               |
| eatment |       |        |       |         |        |               |
| and was |       |        |       |         |        |               |
| dis     |       |        |       |         |        |               |
| charged |       |        |       |         |        |               |
| on      |       |        |       |         |        |               |
| January |       |        |       |         |        |               |
| 11,     |       |        |       |         |        |               |
| 2004    |       |        |       |         |        |               |
| having  |       |        |       |         |        |               |
| com     |       |        |       |         |        |               |
| pletely |       |        |       |         |        |               |
| rec     |       |        |       |         |        |               |
| overed. |       |        |       |         |        |               |
|         |       |        |       |         |        |               |
| ^3)^    |       |        |       |         |        |               |
| Sequest |       |        |       |         |        |               |
| rectomy |       |        |       |         |        |               |
| was     |       |        |       |         |        |               |
| pe      |       |        |       |         |        |               |
| rformed |       |        |       |         |        |               |
| on      |       |        |       |         |        |               |
| April   |       |        |       |         |        |               |
| 20,     |       |        |       |         |        |               |
| 2004.   |       |        |       |         |        |               |
| Ac      |       |        |       |         |        |               |
| cording |       |        |       |         |        |               |
| to      |       |        |       |         |        |               |
| fo      |       |        |       |         |        |               |
| llow-up |       |        |       |         |        |               |
| reports |       |        |       |         |        |               |
| (May 7, |       |        |       |         |        |               |
| 2004    |       |        |       |         |        |               |
| and     |       |        |       |         |        |               |
| June 1, |       |        |       |         |        |               |
| 2004)   |       |        |       |         |        |               |
| pa      |       |        |       |         |        |               |
| tient's |       |        |       |         |        |               |
| co      |       |        |       |         |        |               |
| ndition |       |        |       |         |        |               |
| was     |       |        |       |         |        |               |
| imp     |       |        |       |         |        |               |
| roving. |       |        |       |         |        |               |
+---------+-------+--------+-------+---------+--------+---------------+

## Preliminary findings from retrospective chart review at MD Anderson Cancer Center

A research protocol (Appendix 5) was developed in conjunction with MD
Anderson Cancer Center in Houston, Texas to collect information on the
frequency of osteonecrosis of the jaw in all oncology patients treated
with intravenous bisphosphonate therapy at this center during the
preceding ten year time period. Additional objectives are to:

-   Collect information on cases of altered/delayed healing in the oral
    cavity after oral surgery, miscellaneous trauma, or denture sores in
    patients treated with bisphosphonates.

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-   Develop a better definition of the diagnostic criteria, clinical
    presentation, and natural history of osteonecrosis of the jaw.

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-   Identify risk factors associated with osteonecrosis of the jaw in
    patients treated with intravenous bisphosphonates.

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-   Review records of patients seen in the dental clinics and diagnosed
    with osteonecrosis of the jaw who had been previously treated with
    bisphosphonates.

This initiative will result in the review of the charts of over 4,000
patients in the MD Anderson database who have been treated with a
bisphosphonate at the center over the last 10 years. These charts were
sorted by the pharmacy based on the number of infusions of
bisphosphonates from highest to lowest received at the center and are
being reviewed in this non-random order. The review is ongoing and we
anticipate that it will be completed by the middle of 2005.

We requested an unplanned interim review of the data collected up to
January 12, 2005 to provide information for the ODAC meeting. Of the
first 963 patients' charts that were reviewed by that date, 18 cases of
ONJ were identified. However, there is selection bias because 7 of the
18 cases were reviewed out of sequence, because the treating physician
suspected the presence of ONJ in these 7 patients. In addition, caution
should be used in interpreting these interim results because of the
non-random nature of the chart review. The tumor types included in this
review is shown in Table 4-7 and an overview of the 18 cases identified
is presented in Table 4-8.

###### Table 4-11 Demographics of patients included in the review {#table-4-11-demographics-of-patients-included-in-the-review .unnumbered}

  -------------------------------------------- --------------------------
  **Tumor**                                    **\# of patients**

  Breast cancer                                631

  Multiple myeloma                             148

  Renal cell carcinoma                         32

  Prostate cancer                              18

  Lung cancer                                  17

  Lymphoma                                     13

  Others                                       89

  **Sub Total**                                **948**

  **Non cancer**                               **15**

  **Total**                                    **963**
  -------------------------------------------- --------------------------

###### Table 4-12 Brief overview of 18 ONJ cases from MD Anderson Cancer Center {#table-4-12-brief-overview-of-18-onj-cases-from-md-anderson-cancer-center .unnumbered}

+------------------------------------------+---------------------------+
| **Characteristics**                      | **N (%)**                 |
+------------------------------------------+---------------------------+
| Gender, n (%)                            |                           |
+------------------------------------------+---------------------------+
| Male                                     | 3 (17%)                   |
+------------------------------------------+---------------------------+
| Female                                   | 15 (83%)                  |
+------------------------------------------+---------------------------+
| Age (yrs)                                |                           |
+------------------------------------------+---------------------------+
| Mean (SD)                                | 60.6 (10.9)               |
+------------------------------------------+---------------------------+
| Median                                   | 60.5                      |
+------------------------------------------+---------------------------+
| Range                                    | 42-79                     |
+------------------------------------------+---------------------------+
| Cancer, n(%)                             |                           |
+------------------------------------------+---------------------------+
| Breast cancer                            | 11 (61%)                  |
+------------------------------------------+---------------------------+
| Multiple Myeloma                         | 6 (33%)                   |
+------------------------------------------+---------------------------+
| Medullary Thyroid Cancer^\*^             | 1 (6%)                    |
+------------------------------------------+---------------------------+
| Time since cancer DX to ONJ (months)     |                           |
+------------------------------------------+---------------------------+
| Median                                   | 62                        |
+------------------------------------------+---------------------------+
| Range                                    | 4(A) -- 283(A,Z)          |
+------------------------------------------+---------------------------+
| Bisphosphonate before ONJ                |                           |
+------------------------------------------+---------------------------+
| A only                                   | 3 (17%)                   |
+------------------------------------------+---------------------------+
| Z only                                   | 4 (22%)                   |
+------------------------------------------+---------------------------+
| Z preceded by alendronate                | 1 (6%)                    |
+------------------------------------------+---------------------------+
| A, Z^\*\*^                               | 9 (50%)                   |
+------------------------------------------+---------------------------+
| Unknown                                  | 1 (6%)                    |
+------------------------------------------+---------------------------+
| Time since 1^st^ BP to ONJ               |                           |
| (months)^\*\*^                           |                           |
+------------------------------------------+---------------------------+
| Median                                   | 33                        |
+------------------------------------------+---------------------------+
| Range                                    | 4(A) -- 57(A,Z)           |
+------------------------------------------+---------------------------+
| \* Medullary Thyroid Cancer              |                           |
|                                          |                           |
| \*\*Missing or incomplete info for some  |                           |
| cases. Data is not available on BP       |                           |
| administration outside of MD Anderson    |                           |
| cancer center.                           |                           |
+------------------------------------------+---------------------------+

As shown in Table 4-8, 11 cases of ONJ are breast cancer patients out of
a total of 631 of these patients, while 6 cases of ONJ were identified
among the 148 patients with multiple myeloma.

Among the 18 patients with diagnosed ONJ, various dental problems were
noted in 16 o these patients. Dental extraction or trauma to the jaw
were noted in 11 patients, and 5 patients had mandibular tori or
infection. Fifteen of the 18 patients had received chemotherapy, and the
other 3 patients had hormonal therapy. Details of the 18 ONJ cases are
shown in Appendix 6.

It is noteworthy that 18 cases of osteonecrosis (ON) of other sites were
identified in this review and seven of which had ON prior to
bisphosphonate treatment and 10 had ON after bisphosphonate treatment.
The other case had an unknown history of bisphosphonate treatment.

# Regulatory background

The first spontaneous report of ONJ was received by Novartis in December
2002. Even though based on limited and often incomplete data,
recognition of an increase in the post-marketing surveillance reports of
ONJ in clinical safety database prompted Novartis to act in a timely and
diligent manner to assure safety of the label and patients. As
necessitated by the evolving data for both Zometa and Aredia, and in
advisory consultation with the FDA, Novartis has made several changes to
the Zometa and Aredia package inserts over the last 16 months. The first
update was implemented in September 2003 for Zometa and November 2003
for Aredia. The revised package inserts included a paragraph concerning
ONJ under Post Marketing Experience in the Adverse Reactions section
(see Appendix 7).

After the first case series was published by Ruggiero et al (2004), that
significant awareness of ONJ led to an increase in both the
observation/recognition and reporting. Additional updates to the Zometa
and Aredia package inserts were implemented by Novartis. In February
2004, revised labeling for Zometa was approved by the FDA based on
approval of two NDA supplements which provided extension data from
clinical studies. In this revised package insert, dated March 2004, the
previous statement of September 2003 on the occurrence of ONJ appearing
in the Adverse Reactions Section under Post-Marketing Experience was
updated to reflect understanding of the event and its management (see
Appendix 7).

In May 2004, FDA invited Novartis to a meeting held July 2004 to present
current understanding of ONJ along with available data on risk factors
from any formal assessment of literature including the company's safety
database. This extensive scientific and clinical assessment also
provided opportunity to reassess the package inserts for the two IV
bisphosphonates. Even in the absence of any direct correlation or
causation from mostly limited spontaneous reports data, this exercise
led to further strengthening of the label to assure patient safety. In
the briefing book prepared for the July 2004 meeting, Novartis took the
initiative to propose a third labeling change to include information on
ONJ in the Precautions section. The statement included in the \[Zomedia
Package Insert\] and \[Aredia Package Insert\] is as follows:

**"Osteonecrosis of the jaw (ONJ) has been reported in patients with
cancer receiving treatment regimens including bisphosphonates. Many of
these patients were also receiving chemotherapy and corticosteroids. The
majority of reported cases have been associated with dental procedures
such as tooth extraction. Many had signs of local infection including
osteomyelitis.**

**A dental examination with appropriate preventive dentistry should be
considered prior to treatment with bisphosphonates in patients with
concomitant risk factors (e.g., cancer, chemotherapy, corticosteroids,
poor oral hygiene).**

**While on treatment, these patients should avoid invasive dental
procedures if possible. For patients who develop ONJ while on
bisphosphonate therapy, dental surgery may exacerbate the condition. For
patients requiring dental procedures, there are no data available to
suggest whether discontinuation of bisphosphonate treatment reduces the
risk of ONJ. Clinical judgment of the treating physician should guide
the management plan of each patient based on individual benefit/risk
assessment."**

In addition, Novartis took additional steps to inform the medical
community by mailing a Dear Doctor Letter on September 24, 2004. This
letter was mailed to oral surgeons, medical oncologists, hematologists,
and urologists informing them of the substantive change made to labeling
of the product. This letter was also submitted to the Division of
Oncology Drug Products and to Medwatch.

Similar changes were also made to the Aredia label (and usually followed
the change in the Zometa labeling). In October 2004, the Aredia insert
was updated with ONJ.

Along with changes to the labeling, it was agreed with the Division that
better understanding of ONJ was needed to develop adequate designs for
prospective studies, and in that light Novartis had already contacted MD
Anderson Cancer Center to conduct a retrospective chart review (over the
last 10 years) of all cases on ONJ on IV bisphosphonates. Most of these
efforts have been supplemented with ongoing patient education programs,
described elsewhere in this document as a part of the risk minimization
goal.

# Novartis initiatives concerning reports of ONJ

In response to the reported cases of ONJ, Novartis undertook a detailed
program to collect and review clinical data. The presentation and
documentation of risk factors and follow-up information were collected
to aid physicians in the identification of patients at risk and to
provide guidance for effective patient management.

## Initiation of reporter communications

Many of the ONJ cases reported to Novartis were incomplete and required
follow-up to obtain additional patient information. Reporters were
contacted to obtain complete patient clinical and medication histories
through the use of a specially designed questionnaire (Appendix 8). In
many cases, individual patient data had to be collected from several
sources including oral surgeons, oncologists, and sometimes other
clinicians. The review of patient information revealed the following
risk factors recognized in the medical literature:

See (Appendix 1) for a detailed list of risk factors.

Chemotherapy/hormonal antineoplastic therapy

Coagulopathies

Corticosteroid use

Dental procedures (especially tooth extractions)

Heavy nicotine use

Immunosuppression / status post-transplantation

Local cancerous invasion

Local radiation therapy

Oral herpes infection

Poor oral hygiene

Prior episodes of osteonecrosis / osteomyelitis

## Review and changes of prescribing information

Novartis revised the package inserts for Aredia and Zometa to include
information on osteonecrosis of the jaw described in post-marketing
safety reports. To keep oncologists informed about these changes to the
package inserts, all Novartis Oncology field personnel have been briefed
about the revisions so that they can proactively bring them to the
attention of the healthcare professionals whom they interact with on a
daily basis. In addition, a Dear Doctor letter to health care providers
concerning the recent revisions in the \[Zometa Package Insert\] and
\[Aredia Package Insert\] was sent on September 24, 2004 (a copy of
which is attached in (Appendix 9).

## Advisory boards and patient management

To gain further insight into the prevention, diagnosis, and treatment of
cancer patients with osteonecrosis of the jaw and to understand the
potential role, if any, of bisphosphonates in these patients, Novartis
conducted two advisory board meetings on December 5, 2003 and March 29,
2004. These meetings convened a panel of advisors in the fields of oral
surgery, medical oncology, metabolic bone disease, and dentistry/oral
health (Appendix 10).

The principal outcomes of the first advisory panel were:

1.  Recognition of the multitude of ON risk factors impacting these
    patients

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2.  Recognition of the need for collecting additional information on ONJ
    in cancer patients receiving bisphosphonates as a component of their
    treatment

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3.  Recognition of the need for practical guidelines that would assist
    clinicians in both the medical oncology and dental/oral health
    communities in recognizing, diagnosing and managing cancer patients
    who might be at risk for ONJ or actually have ONJ.

A second meeting of the advisory panel was held specifically to develop
recommendations for patient management. The recommendations are embodied
in a white paper attached in (Appendix 11), and cover these key points:

1.  Identification of risk factors and recommendations for the
    prevention of osteonecrosis of the jaw in cancer patients

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1.  Recommendations for the management of patients who require oral
    surgical procedures prior to or while on bisphosphonate therapy.

2.  Recommendations for the management of cancer patients diagnosed with
    ONJ.

The white paper has been made available through Novartis Medical
Services and Scientific Operations \[distribution of this document began
at the American Society of Clinical Oncology (ASCO) Annual Meeting June
5-8, 2004\]. A final draft manuscript expanding on these recommendations
has been agreed to in principle by the members of the panel and will be
submitted for publication in peer reviewed journals for medical
oncologists, dentists, oral surgeons and allied health care
professionals.

## Change of informed consent

To ensure patients enrolled in or entering trials have access to all new
information, the following addition to the informed consent was included
for worldwide Novartis trials with Zometa effective April 1, 2004:

In advanced cancer patients receiving, among other anticancer
treatments, a bisphosphonate (such as pamidronate/Aredia or zoledronic
acid/Zometa), there have been reports of a condition known as
osteonecrosis of the jaw. This means a portion of the jawbone becomes
permanently damaged, may be painful, and may require dental treatment or
removal of the damaged area. This condition occurs rarely, and may
follow tooth extraction. Because many treatments (such as chemotherapy,
corticosteroids and radiation) and medical conditions or dental
procedures that can increase the risk of osteonecrosis of the jaw may be
administered or occur concomitantly with bisphosphonate therapy, it is
not clear if the reported cases of osteonecrosis of the jaw are related
to the use of bisphosphonates or to these other treatments, medical
conditions or dental procedures.

In addition, Novartis has advised all principal investigators of
investigator initiated trials using Zometa to insert this wording in the
informed consent section and to obtain patients re-consent at the next
scheduled visit.

A similar procedure was implemented for the ongoing trials of zoledronic
acid in benign indications. Novartis is not currently sponsoring or
supporting clinical trials using Aredia.

# Novartis continued due diligence

Novartis remains strongly committed to the safety and welfare of
patients who are being treated with our products.

We will continue to monitor any additional reports of osteonecrosis of
the jaw that may be referred from the medical and dental communities and
to share any insights with health care professionals. These reports will
be promptly provided to the appropriate global regulatory agencies.

In addition, we will continue distribution to healthcare professionals
of the white paper containing guidance regarding prevention, diagnosis,
and treatment of ONJ.

An agreement in principle has been reached by the advisory panel members
on the final content and conclusions of a draft manuscript intended to
discuss the topic of ONJ in greater detail and to be made available to a
wider audience through publication in journals that are widely read by
health care professionals in both the dental and medical communities.
Preliminary discussions have already taken place with journal editors in
both disciplines to seek guidance on the most expeditious means of
publishing these guidelines.

Novartis has also reached out to additional individuals and
organizations for the purpose of receiving input on the design of a
prospective study for further investigations in specific patient groups,
e.g., those with multiple myeloma, to define the clinical course of ONJ
in such patients following bisphosphonate therapy, and to identify
imaging features and other clinical correlates of ONJ. Novartis is
actively reviewing and evaluating these proposals.

In addition, Novartis will include additional steps in protocols
involving cancer patients that will be initiated in the near future for
the purpose of specifying screening dental exams and ONJ monitoring.

Novartis will follow to completion the retrospective study begun last
year at the MD Anderson Cancer Center to gather additional data on the
frequency of ONJ in cancer patients receiving bisphosphonate therapy and
factors that may place patients at risk for developing ONJ as well as
the frequency of ONJ in cancer patients not receiving bisphosphonates
but may have some of the risk factors previously identified.

In an effort to reach out to patients, at a meeting held in late May
2004, Novartis briefed representatives from many of the major patient
advocacy groups in the oncology community on the reports received on ONJ
in patients with advanced cancer treated with bisphosphonates and other
therapies. Representatives of CancerCare, the National Coalition for
Cancer Survivorship, Susan G. Komen Breast Cancer Foundation, Y-ME,
Multiple Myeloma Research Foundation, National Prostate Cancer
Coalition, Us TOO, Alliance for Lung Cancer Advocacy, Support and
Education and the Kidney Cancer Association were all in attendance. To
assist these and other patient organizations in responding to patient
questions, Novartis has prepared and disseminated patient education
materials. In addition, some of the these same groups mentioned above
were contacted again during the time of the annual meeting of the
American Society of Hematology (ASH) in San Diego, CA, December 2004 in
order to provide an update on the topic of ONJ.

Novartis is committed to working with outside experts and health
regulatory agencies to help ensure that patients with ONJ are evaluated
appropriately and that information continues to be provided to
clinicians and patients.

# Novartis assessment and recommendations

## Overall assessment of ONJ

Evaluation of data

ONJ in cancer patients was only sporadically reported in the literature
prior to 2003, with the exception of osteoradionecrosis of the jaw in
head and neck cancer patients receiving radiotherapy. In late 2002,
Novartis first received spontaneous reports of ONJ in patients who were
receiving bisphosphonate therapy. Subsequently, there has been an
increase in the reports of ONJ, with more than 600 reported cases
reported to Novartis as of December 2004. In an effort to better
understand this clinical entity, we have evaluated clinical trial data,
post marketing spontaneous reports, preliminary data from the MD
Anderson retrospective chart review, and literature. All of these
datasets have limitations which prevent firm conclusions from being
drawn, which will be discussed later. As a consequence, a causal
relationship between bisphosphonate use and ONJ cannot be established.

A recent review of the clinical trial database for Zometa and Aredia,
involving over 5,200 patients in pivotal trials, utilizing 18 MedDRA
search terms that could identify cases of ONJ, led to the identification
of six potential cases of ONJ, and 2 cases of osteonecrosis that did not
have location specified. While we cannot rule out underreporting, these
data from controlled clinical trials indicate that ONJ is an uncommon
adverse event.

More than 2.8 million patients are estimated to have received treatment
with Aredia or Zometa, or both worldwide since the products launched. As
of December 7, 2004, 610 spontaneous report of ONJ in patients treated
with these medications have been received by Novartis. A detailed
evaluation of these cases is presented in Appendix 3 and summarized in
Section 4.2.

A retrospective chart review was undertaken at MD Anderson Cancer Center
to try to better understand the natural history of ONJ, the frequency,
and clinical information (risk factors, outcomes) related to this
condition. It was felt that this retrospective study, at a large
institution with comprehensive medical, pharmacy, and dental records,
could provide detailed information about ONJ, which would lead to
hypotheses that could be tested in other studies. This study provides a
clear denominator: patients within the institution that have received
bisphosphonates. Preliminary observations from this study as of January
2005, identified 18 cases of ONJ among approximately 1,000 charts
reviewed so far. Due to limitations and biases described in Section 4.4,
it is premature to draw conclusions about the frequency of ONJ in these
patients treated with bisphosphonates.

The literature on ONJ in bisphosphonate treated patients consists
primarily of case reports and case series, which are described in
Section 4.1 In addition, Durie et al (2004) recently presented
observations from data collected via a web-based anonymous respondent
survey. Durie observed that among the respondents to the survey,
duration of bisphosphonate use is associated with increased risk of ONJ,
that 36 month estimates of ONJ are higher for Zometa versus Aredia, that
other therapies analyzed were not associated with increased risk of ONJ,
and that prior dental problems increase the risk of ONJ.

This web-based survey has a number of limitations. The information was
supplied anonymously by the respondents and therefore cannot be
validated against medical records. The bias associated with this survey
methodology may be significant and has the potential to substantially
affect the study conclusions.

All the datasets (summarized in Table 8-1), with the exception of the
clinical trial database, have limitations in terms of the information
available or are subject to selection bias. The clinical database for
Aredia and Zometa was established at a time when awareness of the
condition was not as great as it is today.

###### Table 8-13 Summary of ONJ for datasets {#table-8-13-summary-of-onj-for-datasets .unnumbered}

+----------+----------+----------+-----+--------+--------+----------+
| **       |          | **N\***  | *   | **By   | **By   | **Du     |
| Source** |          |          | *\# | Tumor  | Drug** | ration/\ |
|          |          |          | of  | Typ    |        | Latency\ |
|          |          |          | C   | e**^†^ |        | (M       |
|          |          |          | ase |        |        | onths)** |
|          |          |          | s** |        |        |          |
+----------+----------+----------+-----+--------+--------+----------+
| Clinical | Pivotal  | Z = 2647 | 6   | 4 MM   | 2 A    | \<1 - 28 |
| Studies\ | (11)     |          |     |        |        |          |
| (# of    |          | A = 1334 |     | 1 PC   | 4 Z    |          |
| trials)  |          |          |     |        |        |          |
|          |          | P = 1234 |     | 1 H&N  | 0 P    |          |
+----------+----------+----------+-----+--------+--------+----------+
|          | Other    | 3067     | 0   |        |        | NA       |
|          | (20)     |          |     |        |        |          |
+----------+----------+----------+-----+--------+--------+----------+
|          | Ongoing  | \~ 8000  | 4   | 1 MM   | 4 mg Z | 4-9      |
|          | (\>100)  |          |     |        |        |          |
|          |          |          |     | 1 PC   |        |          |
|          |          |          |     |        |        |          |
|          |          |          |     | 2 BC   |        |          |
+----------+----------+----------+-----+--------+--------+----------+
| Spon     | Post-m   | 2.8      | 610 | 218 MM | 119 A  | \<1 --   |
| taneous\ | arketing | mil      |     |        |        | 156      |
| Reports  | &        | lion\*\* |     | 125 BC | 248 Z  |          |
|          | Li       |          |     |        |        | Avr --   |
|          | terature |          |     | 267    | 243    | 28       |
|          |          |          |     | Others | both   |          |
|          |          |          |     |        |        | > Z =    |
|          |          |          |     |        |        | > 18‡    |
|          |          |          |     |        |        | >        |
|          |          |          |     |        |        | > A =    |
|          |          |          |     |        |        | > 44‡    |
|          |          |          |     |        |        | >        |
|          |          |          |     |        |        | > A+Z =  |
|          |          |          |     |        |        | > 29     |
+----------+----------+----------+-----+--------+--------+----------+
| MD       | Retro    | 963      | 18  | 11 BC  | 3 A    | 4-57     |
| Anderson | spective |          |     |        |        |          |
| Cancer   |          | (631 BC, |     | 6 MM   | 5 Z    | Median   |
| Center   | Chart    | 148 MM)  |     |        |        | 33       |
|          | Review   |          |     | 1      | 9 Both |          |
|          |          |          |     | Th     |        | > A 4-33 |
|          |          |          |     | yroid\ | 1      | >        |
|          |          |          |     | 1      | u      | > Z 7-25 |
|          |          |          |     | u      | nknown | >        |
|          |          |          |     | nknown |        | > A+Z    |
|          |          |          |     |        |        | > 24-57  |
+----------+----------+----------+-----+--------+--------+----------+
| Durie    | W        | 904      | 62  | MM     | 17 A   | NA       |
|          | eb-based | Res      | \*\ |        |        |          |
|          | Survey   | pondents | *\* |        | 40 Z   |          |
|          |          |          |     |        |        |          |
|          |          | (804 had |     |        |        |          |
|          |          | BP)      |     |        |        |          |
+----------+----------+----------+-----+--------+--------+----------+
|          |          | 299      | 13  | BC     | NA     | NA       |
|          |          | Res      |     |        |        |          |
|          |          | pondents |     |        |        |          |
+----------+----------+----------+-----+--------+--------+----------+
| \*A =    |          |          |     |        |        |          |
| Aredia,  |          |          |     |        |        |          |
| Z =      |          |          |     |        |        |          |
| Zometa,  |          |          |     |        |        |          |
| P =      |          |          |     |        |        |          |
| Placebo  |          |          |     |        |        |          |
|          |          |          |     |        |        |          |
| ^†^ MM = |          |          |     |        |        |          |
| Multiple |          |          |     |        |        |          |
| Myeloma, |          |          |     |        |        |          |
| BC =     |          |          |     |        |        |          |
| Breast   |          |          |     |        |        |          |
| Cancer,  |          |          |     |        |        |          |
| PC =     |          |          |     |        |        |          |
| Prostate |          |          |     |        |        |          |
| Cancer,  |          |          |     |        |        |          |
| H&N =    |          |          |     |        |        |          |
| Head and |          |          |     |        |        |          |
| Neck     |          |          |     |        |        |          |
|          |          |          |     |        |        |          |
| ‡See     |          |          |     |        |        |          |
| Appendix |          |          |     |        |        |          |
| 3 for    |          |          |     |        |        |          |
| lim      |          |          |     |        |        |          |
| itations |          |          |     |        |        |          |
| on the   |          |          |     |        |        |          |
| e        |          |          |     |        |        |          |
| stimated |          |          |     |        |        |          |
| average  |          |          |     |        |        |          |
| duration |          |          |     |        |        |          |
| of       |          |          |     |        |        |          |
| latency  |          |          |     |        |        |          |
| for Z    |          |          |     |        |        |          |
| and A    |          |          |     |        |        |          |
|          |          |          |     |        |        |          |
| \*\*E    |          |          |     |        |        |          |
| stimated |          |          |     |        |        |          |
| based on |          |          |     |        |        |          |
| active   |          |          |     |        |        |          |
| s        |          |          |     |        |        |          |
| ubstance |          |          |     |        |        |          |
| sold     |          |          |     |        |        |          |
|          |          |          |     |        |        |          |
| \*\*\*62 |          |          |     |        |        |          |
| cases of |          |          |     |        |        |          |
| ONJ      |          |          |     |        |        |          |
| among    |          |          |     |        |        |          |
| all 904  |          |          |     |        |        |          |
| p        |          |          |     |        |        |          |
| atients, |          |          |     |        |        |          |
| but only |          |          |     |        |        |          |
| 804      |          |          |     |        |        |          |
| patients |          |          |     |        |        |          |
| had BP.  |          |          |     |        |        |          |
| 57 ONJ   |          |          |     |        |        |          |
| in 804   |          |          |     |        |        |          |
| patients |          |          |     |        |        |          |
| with BP, |          |          |     |        |        |          |
| so 5 ONJ |          |          |     |        |        |          |
| appear   |          |          |     |        |        |          |
| to be in |          |          |     |        |        |          |
| the 100  |          |          |     |        |        |          |
| MM       |          |          |     |        |        |          |
| patients |          |          |     |        |        |          |
| without  |          |          |     |        |        |          |
| BP       |          |          |     |        |        |          |
| t        |          |          |     |        |        |          |
| reatment |          |          |     |        |        |          |
+----------+----------+----------+-----+--------+--------+----------+

Data show a higher reporting frequency of ONJ cases in multiple myeloma
compared to other cancers. Data also indicate a wide range (\<1-156
months) between treatment initiation with bisphosphonates and the onset
of ONJ with an average reported latency shorter for Zometa and than for
Aredia. This estimate is confounded by the recent increase in awareness
of ONJ, the longer period that Aredia has been available to patients
(about 14 years) compared to Zometa (40 months), and the greater current
use of Zometa versus Aredia (70% versus 3%), as well as the bias
inherent in the data collection as previously described.

There are a number of additional issues which confound and limit the
analysis of the datasets above.

-   The lack of a clear case definition for ONJ. The series and reports
    above include a variety of conditions, which make interpretation of
    results difficult.

```{=html}
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```
-   A lack of data on the incidence rate of ONJ in cancer patients not
    treated with a bisphosphonate. Data from the Durie study indicated
    that some respondents in the survey who did not receive
    bisphosphonate reported ONJ suggesting that factors other than BP
    use may contribute significantly to the disease.

```{=html}
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```
-   Recent increase in awareness: the total number of reported ONJ cases
    has increased within the last year, correlating with the increased
    awareness from publications and Novartis actions.

```{=html}
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```
-   Patterns of health care practice may lead to a lack of shared
    information between the dentist or oral surgeon who sees these
    cases, and the oncologist who is caring for the patient medically.

```{=html}
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```
-   The period of time that Aredia and Zometa have been on the market
    differs.. Aredia was approved in the US for hypercalcemia of
    malignancy (HCM) in October 1991 for osteolytic bone lesions of
    multiple myeloma in September 1995 and for osteolytic bone
    metastases of breast cancer in July 1996. Zometa was approved in the
    US for HCM in August 2001 and for the treatment of bone metastases
    in February 2002. Thus there are patients who are long-lived, who
    have had much greater exposure to Aredia than have occurred for
    Zometa.. Also, most patients who were treated with Aredia were
    treated in the period before information on ONJ became widely
    available. These factors may have significant effects on the
    reported difference in the latency of ONJ for Aredia and Zometa.

```{=html}
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```
-   Cancer patients have many risk factors that could lead to
    osteonecrosis, including their cancer treatment. Evolution of
    management of myeloma therapy over time, for example, has included
    the introduction of a number of modalities (thalidomide, velcade,
    transplant) that could potentially be risk factors for ONJ and have
    been introduced in the same period of time that cases have been
    reported.. In addition, the longer the survival becomes the more
    likely that the patients received more cycles of anticancer
    treatment and / or more treatment modalities.

With all these caveats, we have evaluated these datasets to better
understand this condition and to identify hypotheses for future study.
Taken together, these data indicate the presence of significant risk
factors for ONJ in many patients, including smoking, trauma, radiation,
concomitant medications such as chemotherapy and corticosteroids and
prior dental conditions. Notably, prior dental problems appears to be
one of the common characteristics of the majority of the cases, tooth
extraction served as a triggering event in more than half of the
patients, and mandibular tori were noted in several ONJ patients from
the MD Anderson chart review. These are important findings that may help
us to develop strategies to identity patients at risk and develop
prevention strategies to decrease the incidence of ONJ.

## Benefit risk assessment

The high prevalence of bone metastases in patients with advanced
metastatic diseases contributes significantly to the burden of disease.
Bone metastasis are associated with considerable skeletal morbidity
which substantially reduced the quality of life, and in some cases lead
to an increase in mortality.

The clinical benefit of Zometa and pamidronate were clearly demonstrated
in randomized clinical trials. Prior to introduction of bisphosphonate,
\>70% of patients with myeloma and bone metastases from breast cancer
suffered from skeletal related events (SRE) which can cause considerable
morbidity and negatively impact patient's quality of life.
Bisphosphonates have now become a standard of care in patients with
multiple myeloma and breast cancer, and are recommended in the ASCO
guidelines. More recent studies have shown that Zometa is superior to
placebo in the treatment of metastases due to prostate cancer and lung
cancer. Treatment with bisphosphonate cannot only keep a significant
number of patients free of any SREs, it also reduces the overall risk of
developing SREs, i.e, a reduction in the total number of events as well
as an increase in time to each event.

The very strong benefit of Zometa and pamidronate to patients in
reducing, delaying or preventing skeletal complications of their cancer
is undisputed. The condition of ONJ can be a significant medical
condition for some patients. Based on current information and the
experience that the incidence of ORN has also decreased due to
preventive oral hygiene measures and careful dental evaluations, it is
likely that this condition can be managed, if dealt with in accordance
with the guidance put forth by the oral surgeons. We believe that with
these and additional efforts to further elucidate the issue and further
drive knowledge of the management guidelines, the positive risk benefit
of these compounds can be maintained.

Novartis is committed to investigating these reports, and communicating
the findings to physicians and patients. Areas that need further
research include better understanding of the natural history of ONJ,
identification of risk factors that predict for the development of ONJ,
identification of strategies (such as dental care guidelines) which can
prevent the development of ONJ, and guidelines for the optimal
management of ONJ.

## Novartis recommendation

### Additional studies

Based on the discussion above, Novartis recognizes that there is a need
to further investigate and understand ONJ. In that light, Novartis will
be continuing with the ongoing MD Anderson chart review to better
characterize risk factors that might play a role. In addition, Novartis
is considering additional studies to obtain more information about ONJ.
Studies that are being considered (among others):

1.  Data collection on ONJ in ongoing clinical studies

-   Additional data to be collected in ongoing studies on ONJ

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```
-   Additional safety monitoring for ONJ added to a planned
    postmarketing study recently proposed to the FDA assessing treatment
    duration & frequency of dosing post 12 months of Zometa therapy.
    This is a randomized study to determine efficacy and safety in
    \>3000 multiple myeloma and breast cancer patients who have received
    10 or more infusions of Zometa, who will be randomized to receive
    monthly Zometa vs.q 3 month Zometa vs placebo for 12 additional
    months. This study will be initiated in 2005.

2.  Retrospective study in multiple myeloma patients: additional
    retrospective chart review in center that treats myeloma patients.
    We are also exploring additional retrospective studies to look at
    other tumor types. It is critical to identify centers where complete
    medical, dental, and pharmacy records for patients are available.

```{=html}
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```
2.  Prospective study in cancer patients newly treated with
    bisphosphonates assessing natural history of ONJ.

3.  Mechanistic studies to explore potential role of BP use, pending
    further consultation with experts in the field.

### Continue to promote awareness

Novartis will proactively disseminate available information and guidance
to healthcare providers and the patients they care for, to increase the
awareness of ONJ, and to provide management guidelines. It is important
that medical professionals, dentists, and oral surgeons, are aware of
ONJ, and work together to coordinate care. Planned actions include:

-   Distribute the scientific publication derived from the "white paper"
    advisory panel through the field sales force and medical services to
    physicians and nurses and to patient advocacy groups to drive health
    care professional and patient awareness of management guidelines

```{=html}
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```
-   Further support Continuing Medical education activities on ONJ

-   Reconvene the Novartis Advisory Board as necessary to update the
    guidelines

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