Novartis Pharmaceuticals Corporation

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

Zometa^®^ (zoledronic acid) Injection

and

Aredia^®^ (pamidronate disodium) Injection

Submitted: February 1, 2005

Oncologic Drugs Advisory Committee Meeting

March 4, 2005

Property of Novartis Pharmaceuticals Corporation\
All rights reserved\
**Available for public disclosure without redaction**

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

Table of contents [1](#table-of-contents)

List of tables [2](#list-of-tables)

1 Introduction and background [3](#introduction-and-background)

2 Preclinical data [4](#preclinical-data)

2.1 Preclinical pharmacology [4](#preclinical-pharmacology)

2.2 Toxicological studies [6](#toxicological-studies)

3 Review of the drug safety database
[7](#review-of-the-drug-safety-database)

3.1 Methodology [7](#methodology)

3.2 Results [7](#results)

3.3 Discussion [11](#discussion)

4 Conclusions [12](#conclusions)

5 References (available upon request) [13](#references)

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

Table 3-1 Distribution of spontaneous reports by country
[8](#table-3-1-distribution-of-spontaneous-reports-by-country)

Table 3-2 Risk factors [10](#table-3-2-risk-factors)

Table 3-3 Cases with reported biopsy procedures (n=171/610)
[11](#table-3-3-cases-with-reported-biopsy-procedures-n171610)

# Introduction and background

Aredia (pamidronate disodium for injection), is an inhibitor of
bone-resorption belonging to a class of compounds known as
bisphosphonates, developed for use in various diseases of bone and
calcium metabolism. It is approved in the treatment of conditions
associated with increased osteoclastic activity, specifically of
hypercalcemia of malignancy, of Paget's disease of bone, and of
predominantly lytic bone metastases and multiple myeloma. The
international birth date (date of first approval in any country) of this
drug is May 2, 1989, and it is currently marketed in 94 countries. On
the basis of worldwide sales data (942 kg active substance sold), and
assuming a defined total average dose of 500 mg per patient treated, the
exposure from the market introduction until 30 November 2004 was
estimated to be approximately 1,880,000 patients treated. Aredia has
been widely prescribed in cancer patients. For example, in the USA, it
is estimated that, during the period January 1999 to January 2001,
72-82% of multiple myeloma patients and 55-73% of metastatic breast
cancer patients received this drug \[Internal Novartis data October
2003\].

Zometa^®^ (zoledronic acid) appears to be the most potent bisphosphonate
identified to date.

Zometa^®^ has been approved and marketed for two indications:
hypercalcemia of malignancy (HCM) and for prevention of skeletal related
events (pathological fractures, spinal compression, radiation or surgery
to bone, or tumor-induced hypercalcemia) in patients with advanced
malignancies involving bone. Zometa was first registered in Canada on 21
August 2000, followed by Latvia (Baltic States) and Brazil for the
indication treatment of hypercalcemia of malignancy (HCM). The EU
authorization via the Centralized Procedure for this indication was
received on 20 March 2001 and the US authorization was received on 20
August 2001.

The second indication was first registered in Malta on 13 August 2001,
followed by Ecuador and Dominican Republic. The US authorization for
this indication was received on 22 February 2002 and the European
approval was received on 19 July 2002. Zometa is currently approved in
89 countries worldwide.

The estimate of patient exposure was calculated based on worldwide sales
volume in kilogram (22.298 kg) of active substance sold since market
introduction until 30 November 2004, divided by the overall average
dosage of 24 mg per patient (consisting of 6 treatment cycles at a dose
of 4 mg per cycle). Based on this calculation, approximately 929,000
patients received zoledronic acid in the indication HCM and treatment of
bone metastases world-wide in the above period.

Based on market research data (Intrinsiq, March 2004), an estimated
\>85% of breast cancer and multiple myeloma patients in the U.S. with
bone metastases receive an I.V. bisphosphonate, of which approximately
65% of receive Zometa and 35% pamidronate.

In January 2003 Novartis (the sponsor) was informed that an oral
surgeon, Dr. Sal Ruggiero in Long Island, New York (USA), was in the
process of collecting a case series of cancer patients with
osteonecrosis (ON) of the maxillofacial area (ONJ), having in common a
concomitant treatment with Aredia^®^ or Zometa^®^. After repeated follow
up contacts, the sponsor obtained the available case details.
Subsequently, the sponsor was informed that another oral surgeon, Dr. R.
Marx in Miami, Florida (USA), was collecting a similar case series.
Because of these reports, Novartis immediately initiated a comprehensive
medical assessment of ON in cancer patients treated with the company's
bisphosphonates. Previously, overviews and updates on this issue have
been submitted to FDA with the due US Periodic Reports \[Maladorno D,
Breitz B. Zometa Periodic Safety Report. Novartis, March 2003\],
\[Maladorno D, Breitz B. Zometa Periodic Safety Report. Novartis, June
2003\], \[Maladorno D, Eaton K. Zometa Periodic Safety Report. Novartis,
June 2003\], \[Maladorno D, Eaton K. Zometa Periodic Safety Report.
Novartis, September 2003\], \[Maladorno D, Breitz B. Zometa Periodic
Safety Report. Novartis, September 2003\], \[Maladorno D, Breitz B.
Zometa Periodic Safety Report. Novartis, December 2003\], \[Maladorno D,
Eaton K. Zometa Periodic Safety Report. Novartis, March 2004\],
\[Maladorno D, Curtis C. Aredia Periodic Safety Report. Novartis,
December 2003\], \[Maladorno D, Breitz, B. Zometa Periodic Safety Report
Novartis, June 2004\], \[Maladorno D, Eaton, K. Zometa Periodic Safety
Report Novartis, September 2004\], \[Maladorno D, Curtis C. Aredia
Periodic Safety Report. Novartis, December 2004\]. This document updates
the findings for both Aredia and Zometa.

# Preclinical data

## Preclinical pharmacology

It has long been recognized that there is an intimate relationship
between endothelial cells, chondrocytes and osteoclasts, both in the
formation of new bone and during the remodelling of old bone. Vascular
invasion is an essential component of endochondral bone formation, a
process in which bone replaces cartilage through the simultaneous
invasion of osteoclasts and endothelial cells. As chondrocytes
differentiate, they secrete into the matrix factors, such as vascular
endothelial growth factor and transferrin, which induce vascular
invasion. This concept of coupling between the differentiation of
chondrocytes and angiogenesis in the growth plate is supported by animal
studies showing that inhibition of cartilage differentiation disrupts
vascular invasion (Schyipani 1997, Komori 1997). Similarly, inactivation
of VEGF with a specific antibody in young mice suppresses angiogenesis
in the epiphyseal growth plate and impairs trabecular bone formation,
thus indicating that VEGF-mediated capillary invasion is essential for
growth plate morphogenesis and cartilage remodelling (Parfitt 2000).
However, endochondral bone formation and angiogenesis do not appear to
require osteoclast activity. In osteoclast deficient animals
endochondral bone formation and vascular invasion proceed normally in
the absence of any osteoclastic (or chondroclastic) resorption (Deckers
et al, 2002). Angiogenesis also appears to be important for the renewal
of old bone (bone remodelling). In the cortical cutting cone the
actively resorbing osteoclasts are usually located at the tip of
sprouting capillaries, and in trabecular bone osteoclasts are in close
contact with endothelial cells (Gerber, et al 1999).

Against this background of a close association between osteoclasts and
endothelial cells, it is pertinent to consider the potential effects
that inhibitors of osteoclast activity, such as bisphosphonates, might
exert on angiogenesis. Recently several nitrogen-containing
bisphosphonates (pamidronate, ibandronate, risedronate, zoledronate)
have been shown to inhibit angiogenesis in non-mineralized tissue in
various rodent models (Wood 2002, Fournier 2002, Fournier 2003). The
mechanism of this soft tissue effect of bisphosphonates has yet to be
elucidated. Bisphosphonates rapidly bind to bone and have a short plasma
half-life, as a result there is only a low, transient exposure of
non-mineralized tissues to drug. Despite the fact that bisphosphonates
accumulate in bone, there are no data to suggest that that these
compounds inhibit angiogenesis of normal vessels or induce osteonecrosis
in vivo when given at pharmacologically relevant doses. However, there
is a report \-- yet to be independently confirmed \-- that pamidronate
treatment can induce a modest blood flow reduction in the tibia and
distal femur of young female rats (Kapitola and Zak 1998). By contrast,
both short- and long-term studies in rats and monkeys, have produced no
evidence that administration of pamidronate or zoledronate at doses
which markedly suppressed bone resorption exerted any deleterious effect
on bone (Pataki 1997, Hornby 2003, Azuma 1998, Binkley 1998, Bouquot
2000, External Study Report MIN 955041). On the contrary, recent data
indicate that zoledronate exerts a beneficial effect in 2 rat models of
osteonecrosis by preserving femoral head structure while
revascularization occurs (Little 2003a, Little 2003b). Moreover,
preliminary data from a rat fracture repair model indicate that
zoledronate treatment does not delay endochrondral ossification, a
process that requires revascularization (McDonald, Zulai and Little
2004).

In contrast to the above findings obtained in animal models of benign
bone disease, zoledronate has been shown to reduce micro vessel density
in the bone lesions of mice bearing the 5T2 myeloma cell line (Croucher,
et al 2003). However, the dose schedule used in this study, 120 µg/kg SC
twice a week, corresponds to more than ten-fold the human 4 mg dose and
the vessels investigated were predominantly tumor vessels.

Although bisphosphonates have primarily been developed for the treatment
of osteoporosis and bone metastases, they have also been investigated as
a potential therapy for periodontitis. Several preclinical studies have
indicated that bisphosphonates (risedronate, pamidronate, alendronate,
neridronate) can inhibit the elevated alveolar bone loss associated with
experimental periodontitis in a variety of animal models (Shoji 1995,
Shibutani 2001, Reddy 1995, O'uchi 1998, Weinreb 1994, Brunsvold 1992).
In these studies there was no evidence of osteonecrosis of the jaw bones
despite bisphosphonate treatment lasting for up to 6 months at doses of
up to an order of magnitude greater than those approved for clinical
use.

Apart from the specific dental studies, there is very little preclinical
literature on the effects of bisphosphonates on bone metabolism in the
jaw. In a histomorphometric study comparing bone turnover in the humerus
and mandible of aged ovariectomized rats, risedronate (dosed SC for 10
weeks at approximately twice the equivalent oral human weekly dose for
osteoporosis treatment) markedly reduced bone formation rates on the
endocortical surface of the humerus and the endosteal surface of the
mandible. By contrast, there was little effect on bone turnover at the
periosteal surface of either the mandible or mid-shaft humerus
(Hunziker, Wronski and Miller 2000).

These data suggest a differential sensitivity of bone turnover to
bisphosphonate inhibition at different sites within a particular bone,
but do not indicate that the overall response pattern of the mandible is
any different from that of the humerus.

In conclusion, there is no evidence from the preclinical studies that
either pamidronate or zoledronate affects angiogenesis during bone
formation or bone remodelling in normal or estrogen-deficient animals.
The observation that bisphosphonates inhibit angiogenesis in soft
tissues and in myelomatous bone lesions implies a tissue-specific
response to bisphosphonates, and this observation does not appear to be
generalizable to the jaw bone. Moreover, there has been no published
report of osteonecrosis in animal models, in the axial or appendicular
skeleton or in the jaw bones, associated with either pamidronate or
zoledronate or indeed any other bisphosphonate. On the contrary,
pamidronate and zoledronate are now being used in pilot clinical trials
for the prevention and treatment of osteonecrosis. Finally, it is
interesting to note that, in the absence of bisphosphonate treatment,
marked changes in blood flow and vascularization of the mandible have
been noted in a monkey model of experimental inflammation of the
mandible, as well as in chronic osteomyelitis of the jaw in humans
(Wannfors 1989, Wannfors 1991).

## Toxicological studies

A comprehensive pre-clinical safety assessment has been performed for
pamidronate and zoledronate that includes a wide range of oral and
parenteral toxicology studies in multiple species at doses comparable to
and at many mulitples of those typically administered to the oncology
patient (90 mg pamidronate, 4 mg zoledronate). These studies included
acute studies in three species; repeat-dose subchronic and chronic
studies in two species, including extensive IV infusion studies in the
dog; reproductive studies in two species; 2-year carcinogenicity studies
in two species; in vivo/in vivo mutagenicity studies; and additional
special studies including local irritation, dermal, etc.

Nonproliferative hyperostosis of the metaphyseal junction in growing
animals is a change produced by all bisphosphonates, including
pamidronate and zoledronate. It was observed in virtually all treated
animals in the pre-clinical safety studies and involved a lengthening of
the growth plates as a consequence of a reduction in osteoclastic bone
resorption, clearly a pharmacological effect. Degenerative bone findings
similar to those described for osteonecrosis in humans have not been
observed following pamidronate administration. The only osseous changes
of a degenerative nature seen with zoledronate occurred in a pilot study
in dog wherein exposure at the level of bone was estimated to be very
high (30 - 80x therapeutic human dose, daily for up to one week) (Longo
2002). In this study bone focal lesions were observed at the metaphyseal
junction (growth plates) of rib and femur, the two bones evaluated
histologically. They were characterized by osteoclast karyorrhexis and
increased mitotic activity, hemorrhage, edema, necrosis, inflammation
and two instances of an accompanying periosteitis. The etiology was
attributed to concomitant gastrointestinal ulceration produced by the
zoledronate oral formulation being tested resulting in direct, unimpeded
systemic exposure affecting the growth plates of these developing
animals. It is known that bone is the recipient of up to 60% of the
administered dose of zoledronate. Moreover there is a propensity for
zoledronate to further concentrate in those areas of bone where growth
and remodeling is greatest such that these osseous changes were not
unexpected.

Based upon microanatomy and anatomic location, the bone finding
described as osteonecrosis of the jaw in the human (Marx and Stern 2002)
bears no morphological resemblance to those bone changes described in
the latter animal study. Moreover a careful search of the literature did
not reveal any known association between bisphosphonate administration
and the phenomenon of osteonecrosis in animals. Animal experiments to
study the possible role of bisphosphonates (including pamidronate and
zoledronate) in the etiology and pathogenesis of ONJ were considered.
However, it was concluded that the design and conduct of such studies
would be extraordinarily complex taking into account this condition's
multifactorial etiology and traumatic (e.g. tooth evulsion studies in
the canine) yielding what could at best be considered equivocal results.

# Review of the drug safety database

## Methodology

The Novartis worldwide spontaneous reports drug safety database for
Aredia and Zometa was searched for the following MedDRA Version 6.1
preferred terms:

\'osteomyelitis\', \'osteomyelitis acute\', \'osteomyelitis chronic\',
\'osteomyelitis drainage\', \'aseptic necrosis bone, \'osteonecrosis\',
\'bone infarction\', 'necrosis', \'sequestrectomy\', \'primary
sequestrum\', \'secondary sequestrum\', \'tertiary sequestrum\',
'maxillofacial operation', 'jaw operation', 'mandibulectomy', 'oral
surgery', 'jaw lesion excision', 'bone debridment'.

The primary reporters of osteonecrosis of the jaws have been using
interchangeably terms suggestive of osteonecrosis and terms suggestive
of osteomyelitis and other jawbone infections. In fact the assumption
has been made that, cases presenting with signs and symptoms of
maxillofacial bone infection previously experienced an otherwise
non-documentable primary vascular event. The drug safety database indeed
appears to be made up of reports with a combination of various terms
associated with these etiologically different conditions. Therefore, the
search was designed to capture both.

The cut-off date of the search was from introduction until December 7,
2004 (date of case creation in the drug safety database). The selected
cases were printed in detailed line listing format and medically
reviewed in order to eliminate cases proven not to be or unlikely to
refer to osteonecrosis of the maxillofacial area.

## Results

The drug safety spontaneous reports database search screening identified
610 reports of patients experiencing signs and symptoms suggestive of
osteonecrosis and/or osteomyelitis of the maxillofacial area:

-   120 reports noted Aredia as the only suspect drug (including one
    case with Zometa in the medical history),

-   in 116 reports both Aredia and Zometa were reported as suspected
    (the two drugs were given most frequently sequentially, but in a few
    cases the treatments were switched, sometimes more than once)

-   374 reports noted Zometa as the suspect drug. Of these 374 reports,
    126 reported Aredia in the treatment history

In 8 cases out of the 610, the patients also received oral
bisphosphonates concomitantly or prior to the IV bisphosphonate
treatment.

Two reports (PHEH2003US02597 with Aredia and PHEH2003US02566 with
Zometa) refer to the same patient. In one case it is unknown if the
patient received Aredia or Zometa (PHEH2003US04611: for the purpose of
the analyses done, this case was handled as if both drugs were
administered).

The first report of osteonecrosis of the jaws was received by the
sponsor in December 2002, while reports from sources outside the US have
been received only since February 2004.

The country of origin of the reports is displayed below:

###### Table 3-1 Distribution of spontaneous reports by country {#table-3-1-distribution-of-spontaneous-reports-by-country .unnumbered}

  --------------------------- -------------------------------------------
  Country                     Number of reports

                              

  Australia                   7

  Belgium                     25

  Brazil                      18

  Canada                      7

  Chile                       2

  France                      2

  Germany                     55

  Greece                      1

  Israel                      11

  Italy                       14

  Mexico                      1

  Norway                      4

  Singapore                   1

  S.Africa                    1

  Spain                       12

  Sweden                      1

  UK                          1

  USA                         440

  Switzerland                 7

  TOTAL                       610
  --------------------------- -------------------------------------------

Of the 610 reports, the majority (557) reported the adverse event term
of osteonecrosis, in association with a variety of other maxillofacial
abnormalities, particularly osteomyelitis, which frequently was the
presenting clinical picture of the patient at time of diagnosis.
"Impaired healing" following dental extractions was often the first
abnormality which led to a subsequent diagnosis of osteomyelitis or
osteonecrosis. Twenty seven reports had a documented actinomycotic
infection of the maxillofacial lesion.

The most common osteonecrosis or osteomyelitis location was the mandible
(222/610 reports), followed by the maxilla (69/610). The remaining cases
had other or unspecified maxillofacial localization, including a generic
localization to the "jaw". Some reports did not specifically mention a
maxillofacial localization of the lesion, but based on the contest of
the information (e.g. when received from maxillofacial surgeons), they
have been interpreted as having such location.

The current tally of the type of reports is as follows: 531 spontaneous
reports and 79 literature cases. Most reports were initially received as
spontaneous reports by the sponsor. However, the two primary reporters,
Drs. Marx and Ruggiero, have also collected information on a large
number of cases seen by others, and included them in their publications
(Marx 2003, Ruggiero 2004). Several cases were consequently
re-classified as literature cases. It is also possible that some of the
patients mentioned with few details in Dr. Ruggiero's paper (Ruggiero,
et al 2004), were actually already included in Novartis' safety
database. Several reporters have in fact contacted both Novartis and Dr.
Ruggiero providing information on their cases. However, for lack of
details available in Dr. Ruggiero's database, an exact match with
existing cases was not always possible.

Most of the reports occurred in females (340/610, 56%) while 231/610
(39%) occurred in males. In 39 cases the gender was not reported.

Age was not reported in 142 reports. Among the remaining 468, the mean
age was 64 years (range 27-93). When stratified by gender, the mean age
was 62.6 for females (n=281, range 27-93), and 66.4 for males (n= 182,
range 41-89).

Aredia and Zometa were prescribed for the following indications:
multiple myeloma (218) breast cancer (125), bone metastases (110),
prostate cancer (37), osteoporosis (13, of which nine reported
concomitant cancer), hypercalcemia (6), oral neoplasm (2), lung cancer
(3), uterine cancer (1), CML (1), renal cell carcinoma (2), breast and
ovarian cancer (2), lymphoma (4), Paget's disease (1), unspecified
cancer (6) and unknown diagnosis (79).

It should be noted that this type of information is often quite vague,
and that typically both the oral surgeons and the sponsor experienced
difficulties in integrating the case information pertinent to the oral
events with the information available to the family dentists and to the
prescribers of the bisphosphonate therapy, which often did not respond
to the requests for additional clarifications. Consequently, the
information on parameters such as indication, dosage and duration of
treatment is often vague or incomplete or sometimes contradictory,
despite the sponsor's efforts to collect it.

In 251/610 (41%) of the reports there is an unknown duration of
bisphosphonate treatment and/or the date of the event diagnosis is not
available, therefore information on the temporal relationship can not be
confirmed.

However, in 359/610 (59%) of the reports the information regarding the
treatment and the event dates was available, and a calculation of the
time from bisphosphonate treatment start to onset of osteonecrosis
(reported diagnosis or first symptoms) was possible.

In cases where the patient switched from one drug to the other,
including cases reported only with one suspect drug, we calculated the
total time from the treatment start (Aredia or Zometa) until the
establishment of the diagnosis or until the first symptoms indicative of
osteonecrosis (eg impaired healing after tooth extraction, bone
exposure, etc.).

The time interval between initiation of the bisphosphonate treatment
(Aredia or Zometa) to AE onset, for these 359 reports , ranged from \<1
week to 626 weeks (\<1 to 156 months), and averaged 28 months. When
stratified by treatment group (without adjusting for biases such as
different time of drugs on the market), the time interval between
initiation of the bisphosphonate treatment to AE onset, averaged 44
months for the assessable patients who received only Aredia (64/359,
18%), 29 months for the patients who received both Aredia and Zometa
(177/359, 49%), and 18 months for the patients who received only Zometa
(118/359, 33%).

In 303 (50%) of the cases potential triggering events like dental
surgery, local trauma, tooth extraction or dental infection were
reported, preceding the diagnosis of ONJ.

In 450 (74%) of the reports the patients had at least one of the below
listed risk factors. It should be noted that several reports were
initially provided to the sponsor lacking information on risk factors,
which were subsequently found after follow-up. Similarly, it can be
assumed that cases without apparent relevant risk factors, particularly
the ones received more recently, may have been incompletely documented.
For example, with respect to the patient population with metastatic
cancer, it is expected that the vaste majority of the patients have
received chemotherapy (and additional corticosteroids in the multiple
myeloma subset).

###### Table 3-2 Risk factors {#table-3-2-risk-factors .unnumbered}

+----------------------------------------------+-----------------------+
| **Reported Risk Factors**                    | **Number of Reports   |
|                                              | (%)**                 |
+----------------------------------------------+-----------------------+
| Corticosteroids(concomitant or in medical    | 230 (38%)             |
| history)\*                                   |                       |
+----------------------------------------------+-----------------------+
| Chemotherapy (concomitant or in medical      | 315 (52%)             |
| history)\*                                   |                       |
+----------------------------------------------+-----------------------+
| Hormonal therapy                             | 63 (10%)              |
+----------------------------------------------+-----------------------+
| Radiotherapy to the head and neck area       | 28 (5%)               |
+----------------------------------------------+-----------------------+
| Anemia                                       | 89 (15%)              |
+----------------------------------------------+-----------------------+
| Thalidomide                                  | 89 (15%)              |
+----------------------------------------------+-----------------------+
| Transplant                                   | 57 (9%)               |
+----------------------------------------------+-----------------------+
| Other\*\*                                    | 263 (43%)             |
+----------------------------------------------+-----------------------+
| \*in 188 (31%) reports the patients had both |                       |
| corticosteroids and chemotherapy             |                       |
|                                              |                       |
| \*\* broad criteria used including all       |                       |
| conditions and medications with potential    |                       |
| impact on bone metabolism. See reference 1.  |                       |
+----------------------------------------------+-----------------------+

Among the 263 reports with "Other" risk factors included in the table
above, three had a prior Herpes infection of the maxillofacial area.

The case narratives were reviewed for information pertaining to bioptic
procedures, with the following results:

###### Table 3-3 Cases with reported biopsy procedures (n=171/610) {#table-3-3-cases-with-reported-biopsy-procedures-n171610 .unnumbered}

  ----------------- ------------------- ------------------- ----------- ---- -----------
                    **Osteonecrosis**   **Osteomyelitis     **Other**        **Total**
                                        without                              
                                        osteonecrosis**                      

                                                                             

  Aredia            19                  12                  21               52

  Aredia and Zometa 17                  15                  6                38

  Zometa            36                  24                  21               81

                                                                             

  Total             72                  51                  48               171
  ----------------- ------------------- ------------------- ----------- ---- -----------

Of the cases with reported biopsy results, only one was found to
possibly have metastatic disease (PHEH2004US03342).

## Discussion

Age is a significant factor associated with ON of the maxillofacial
area. It has been published that in a case series of 35 consecutive
cadaver jawbones of elderly humans, almost a third had microscopic and
macroscopic evidence of ischemic damage of the bone (Bouquot and McMahon
2000). The risk related to age is also associated with risk dependent on
gender: in the general population, it is estimated that women 65 years
and older have a rate of ON of the jaws more than twice higher than
women 25 to 65 of age (Bouquot and McMahon 2000).

The mean age of two maxillofacial ON case series reported in the
literature was around 50 years of age (Shankland 2002), with a
predominance of females. When the demographic characteristics of the
published case series of maxillofacial ON is compared with the
demographics of the cases reported to Novartis, it can be noted that the
gender distribution of the latter is within the expected limits (56%
females), while the mean age is substantially higher (61.7 years old
versus the published average in the early 50s). The gender distribution
in the reported cases may however be confounded by the use of the drug
in gender-specific cancers such as breast or prostate.

Bisphosphonate recipients are primarily cancer patients. From the above
considerations it can be inferred that, in addition to factors such as
chemotherapy, steroids, anemia, and increased risk of oral infections,
the cancer population is at risk of developing ON also because it is
typically comprised of patients of relatively advanced age. 218/610
(36%) of the reported cases had multiple myeloma, which can be
associated with serum hyperviscosity (Longo 2001), and it may represent
a risk factor for ON. Many of the cases reported to Novartis have
received corticosteroids therapy. While this has been specifically
reported only for some patients, in many other cases it can also be
inferred from the underlying cancer diagnosis. Consistently with the
published literature, in an epidemiological study conducted by Novartis
(Sablinska 2003), the risk of osteonecrosis in systemic corticosteroid
users was almost 4 times higher than in non users.

The analysis of time from initiation of bisphosphonate treatment to
onset of ONJ provided different average estimates for the patients who
only received Aredia, and the patients who only received Zometa. It
should be noted however that the data may be confounded by known factors
such as cancer history and stage, prior or concurrent corticosteroid and
chemotherapy. Chemotherapy regimens have been changing over time, and
may differ by geographical location. In addition, it is likely that the
different time on the market of the two drugs, and the recent increased
awareness on osteonecrosis consequent to the Novartis initiatives and
published reports, may have biased the data.

It should be noted that in the patients who received both drugs
sequentially, the average time from drug initiation until event onset
for the individual bisphosphonate drug did not differ significantly from
the subgroups who received only one of the IV bisphosphonates.

# Conclusions

The majority of the cases of maxillofacial osteonecrosis reported to
Novartis were identified by reporters who suspect Aredia^®^ or Zometa^®^
as the primary cause of this event. The following evidence should
however be weighted against this hypothesis:

-   The clinical case information available to a large proportion of the
    reporters appears to be affected by selection bias, and to be
    extremely 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. Overall, it appears that most the 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 in order to obtain the maximum level of
    information available.

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-   Cases of osteonecrosis of the maxillofacial area have to be expected
    in the cancer population, because of the simultaneous effects of
    multiple and significant risk factors: corticosteroids,
    chemotherapy, transplant, radiotherapy, dental infections and
    procedures, relatively advanced age.

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-   Since cancer patients with bone involvement are routinely treated
    with bisphosphonates, the concurrence of bisphosphonate use and ONJ
    is not surprising, and it does not establish a causal relationship..
    In the USA, it is estimated that, during the period January 1999 to
    January 2001, 72-82% of multiple myeloma patients and 55-73% of
    metastatic breast cancer patients received Aredia. Since its market
    introduction, Zometa became the most frequently used bisphosphonate
    for the treatment of bone metastases, with a \>65% unit share of the
    bisphosphonate market \[Internal Novartis data October 2003\]. It
    is, therefore not unexpected that an increasing number of the
    recently reported cases of osteonecrosis have been seen in patients
    treated with Zometa, in line with current medical practice.

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-   Aredia has been used extensively for years, since it was first
    introduced in the worldwide market since 1989. As of the end of
    November 2004, it is estimated that approximately than 2.8 million
    patients have been treated with Aredia or Zometa. No spontaneous
    reports associating ON with these drugs have been provided to the
    sponsor prior to December 2002. After the introduction of Zometa,
    Aredia sales have been declining: it is to be expected that in the
    future the number of adverse event reports associated with this drug
    will be declining as well.

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-   The preclinical and toxicological studies do not suggest that
    inhibition of osteoclastic activity is associated with the onset of
    a significant deficit in bone vascularization. The specific effects
    on angiogenesis seen in some specific experimental conditions do not
    appear to be applicable to the clinical use of bisphosphonates.

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-   The recently observed increase in reporting and probable earlier
    diagnosis (in some cases over- diagnosis) could be explained by the
    increased awareness, presentations at scientific meetings and
    Advisory Board meetings including the primary reporters and
    representatives of other disciplines. Osteonecrosis of the jaws has
    an unknown latency period, and may remain asymptomatic for many
    weeks or months and may only be recognized by the presence of
    exposed bone in the oral cavity. These lesions typically become
    symptomatic when sites become secondarily infected or there is
    trauma to adjacent and/or opposing soft tissues via the sharp or
    rough surfaces of the exposed bone.

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-   Given also the different reporting sources (including publications,
    oral surgeons, clinical oncologists, consumers and Health
    Authorities), there is a high likelihood that the Novartis safety
    database includes duplicates.

Based on the above, Novartis does not believe that there is sufficient
evidence of a causal association between Aredia or Zometa and
osteonecrosis. However, in the interest of patient safety and physician
awareness, the USPI has been amended for both drugs to reflect that
reports of osteonecrosis have been received by the sponsor. The issue
will require continuous monitoring, and additional follow-up efforts for
the cases already reported.

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