Pharmacovigilance of jaw osteonecrosis.

Bisphosphonate-related osteonecrosis of the jaw: an

Italian post-marketing surveillance analysis

Laura Sottosanti

Roma 12th october 2013

 Public Declaration of transparency/interests*
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*Laura Sottosanti, in accordance with the Conflict of Interest Regulations approved by AIFA Board of Directors (26.01.2012) and published on the
Official Journal of 20.03.2012 according to 0044 EMA/513078/2010 on the handling of the conflicts of interest for scientific committee members and
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N.B. I am not receiving any compensation

Bisphosphonates (BPs) are widely used in the management
of diseases characterized by high bone turnover because of
their capacity to slow the bone remodeling process.

They are extensively used in cancer-related bone disease,

osteoporosis and Paget’s disease, and they have also been
administered in such rare conditions as osteogenesis
imperfecta and widespread forms of secondary osteopenia.
 Bisphosphonates are synthetic pyrophosphate analogs generally grouped
into two classes according to their chemical structure and mechanism of
action:

- non nitrogen-containing BPs (e.g. clodronate)

- nitrogen-containing BPs (alendronate, ibandronate, pamidronate,
risedronate and zoledronate)

Both nitrogen- and non nitrogen-containing BPs induce suppression of

osteoclast function, promotion of osteoclast apoptosis and inhibition of
osteoclast formation and recruitment.
• Although BPs are used to treat and prevent skeletal-
related events and preserve bone mineral density,
their use has been associated with a subset of
skeletal complications, namely

– osteonecrosis of the jaw (ONJ) and

– atypical femoral shaft fractures

BP-related ONJ (BRONJ) is clearly established as an important safety issue in BP-treated patients.

Despite a series of studies have been conducted, little is known about this complication in terms of
The European Medicines Agency (EMA) has included the
study of BP-induced adverse skeletal events, including
BRONJ, among the 2013 priorities for drug safety
research.

Specifically the Agency has encouraged observational

studies using existing databases and registries
Although BRONJ emerged during the post-marketing phase,
regulatory pharmacovigilance databases have been used
only in a few previous studies .

The national spontaneous reporting systems are crucial

components of post-marketing drug safety surveillance.
 Italian pharmacovigilance system
Patient
Adverse reaction
From paper reporting form to the network Suspected drug
Concomitant drug
ADR Clinical history.
Other substance used
Reporter
Follow up
As soon as possible
7days

Reporter
• Observes the reaction
• Fills the form
• Provides follow-up
• Provides a clinic assessment in
case of serious reaction
National Pharmacovigilance
Pharmacivigilance Responsible :
• Checks completness of data Network- RNF
• Codifies and data entry
• Feed-back at reporter
Local PV Responsible available on AIFA website:
http://www.agenziafarmaco.gov.it/it/responsabili
Local PV Responsible available on AIFA website:
http://www.agenziafarmaco.gov.it/it/responsabili
 REPORTING FLOW
Reporter

Pharmacovigilance Requests of
follow-up
Responsible

NNP
Authomatic Pharmaceutical
E-mail companies

WHO
REGIONS

AIFA PSUR
Pharmacovigilance Office
Bisphosphonate-related osteonecrosis of the jaw:
an Italian post-marketing surveillance analysis in
collaboration with Second University of Naples
 Aim

Analyse all cases associated with the standardized MedDRA

query (SMQ) for osteonecrosis (ON) after BPs administration
reported to the Italian Pharmacovigilance Adverse Event
Spontaneous Reporting System [Rete Nazionale
Farmacovigilanza] (RNF) beetween 2003 and 2011.
 Methods

SMQ: By applying an SMQ for ON, we retrieved both reports

codifying the AE as “ON” or “ONJ” (all reports codifying “ON”
referred to the jaw) and those codifying the AE as a term
related to signs, symptoms, diagnoses, syndromes, physical
findings, laboratory and physiological test data associated with
ON.

All reports were assessed case-by-case in terms of quality and

reliability of the data reported, type of BP, BP exposure time,
BP dose and time since last use.
 Statistics Methods
• Median BP exposure times were evaluated using the Kruskal-
Wallis nonparametric ANOVA test to look for significant
differences among the various BP type patient groups
because the conditions required to perform a one-way
analysis of variance (ANOVA) were not fulfilled.

• Dunn’s post hoc test was used to determine which groups

were significantly different. Analyses were performed with
SPSS software (version 18.0.0).
 Annual number of ONJ report after BP
treatment recorded by RNF from 2003 to 2011
723 reports of ONJ or
possible ONJ after BP
treatment

554 169
(76,62%) (23,38%)
reports: AE reports: AE
coded with coded with
ONJ or ON medical term
related to
ONJ
Number of ONJ reports according to type of BP

636 (87.97%) related

to only one BP

87 (12.03%) related
to 2 or 3 different BP

547 (75.66%) Zoledr.

112 (15.49%) Alendr.
93 (12.86%) Pamidr.
 Patient characteristics

78.01% of ONJ cases concerned cancer patients and

18.81% patients affected by benign conditions
 Time of BP exposure before ONJ onset

A total of 618 reports were included in the analysis of

duration of BP exposure.

In fact, we excluded reports if they were fewer than 3

days for a given BP type or if they missed data regarding
duration of BP exposure
Time of BP exposure before ONJ onset
BP dose exposure before ONJ onset

Of the 723 ONJ cases retrieved, dose

information was missin in 248 cases
Time course of ONJ onset in each BP group
Time elapsed between BP last dose and event onset
 Conclusions

• The study confirms the importance of national spontaneous

reporting systems and highlights the contribution of healthcare
professionals in reporting suspected adverse drug reactions.

• ONJ can occur very soon not only after zoledronate and
pamidronate administration, but also after alendronate,
ibandronate and clodronate administration
 Conclusions

• this is the first study to evaluate how recently BP was used before
ONJ or possible ONJ onset. Based on this analysis, we have
classified ONJ or possible ONJ cases in two groups, i.e. those who
have experienced the AE while on therapy, and those who
experienced it after therapy cessation.

• this finding raises the urgent issue of how to monitor those patients
who have been treated with BP and could to be at risk of
developing ONJ also after cessation of therapy.
 Proactive pharmacovigilance

PhV is not only a responsibility of regulatory agencies, but

mostly of the health system:
 Healthcare provider organisations should be responsible for following
up closely the effectiveness and safety of new medicines to be used

Excellence in pharmacovigilance consists in preventing drug-

induced disease, rather than assembling high numbers of cases
 Thank you for your attention

CONTATTI

Tel 06 59784329
E-mail: l.sottosanti@aifa.gov.it
www. Agenziafarmaco.it