National outcomes study of patients with osteonecrotic jaw (onj) amongst patients referred to dental hospitals and mfu/ent hospital departments in england and referred during 2009 and 2010

PROTOCOL

A 2-year national new patient registration of patients with avascular necrosis of the
jaws including bisphosphonate-related osteonecrosis’ (BRONJ) referred to Oral
Surgery, Oral Medicine, Oral and Maxillofacial Departments and Dental Hospitals in
England, Wales, Scotland and Northern Ireland

Purpose of proposed study
1) To capture all new patient referrals (case-series) with avascular necrosis of the jaws including bisphosphonate-related osteonecrosis necrosis’ (BRONJ) to Oral Surgery, Oral Medicine, Oral and Maxillofacial Departments and Dental Hospitals in England, Wales, Scotland and Northern Ireland from 1st June 2009 to 31st May 2011. 2) To estimate national incidence using national estimates of population, overall and 3) To collect data on medical and social history, medications history in particular the use of bisphosphonates (e.g.type of bisphosphonate, cumulative dose), other risk factors such as smoking, periodontal health, referral pathway, clinical presentation and causation e.g. recent dental extraction. 4) To collect 12 months treatment and outcome data on all these referrals 5) To investigate potential risk factors in relation to patient outcome
Please note: Registration includes any case of ‘avascular’ jaw necrosis present for
greater than 8 weeks irrespective of whether the patient is on bipshosphonates or
not. The diagnosis should not include 'conventional' osteomyelitis nor
osteoradionecrosis

Why is this study necessary
Bisphosphonates are a class of agents used in the management of osteoporosis
(treatment and prophylaxis), Paget’s disease, malignancies involving bone (e.g. myeloma,
breast cancer, prostate cancer) and tumour induced hypercalcaemia.1 The efficacy of
these agents in treating and preventing the significant skeletal complications associated
with these conditions has had a major positive impact for patients and is responsible for
their widespread use in medicine.
Despite these benefits, BRONJ has emerged as a significant complication in a subset of
patients receiving these drugs, with reports of BRONJ in patients receiving long-term
bisphosphonate therapy appearing in the literature since 2003. 2
Most cases of BRONJ have been reported in cancer patients receiving the intravenous
aminobisphosphonates zoledronic acid and pamidronate. 3-6 More recently there have
been reported cases of BRONJ related to oral administration of bisphosphonates, used
mainly in the treatment and prevention of age related osteoporosis.7-9 Osteoporosis is
estimated to affect around 3 million postmenopausal women in the UK, over one million of
these have had a confirmed diagnosis of osteoporosis after a dual-energy x-ray
absorptiometry (DXA) scan.10Prevalence increases markedly with age and after the
menopause and approximately 30% of women in England and Wales aged 80years and
older are estimated to have osteoporosis. It is estimated that 10-20% of women with
osteoporosis receive drug treatment for the condition.11 The total number of women
receiving medication for osteoporosis is approximately 480,000. This equates to 23% of
the female population who are expected to be suffering from osteoporosis.3
Events that appear to precipitate BRONJ include a history of trauma (extractions), dental
surgery or dental infection. With intravenous bisphosphonate administration; in addition,
the extent and duration of exposure to bisphosphonates seems to correlate with the
risk.12 The cumulative risk from long-term oral bisphosphonates is unknown. Other risk
factors to developing BRONJ seem to be steroid treatment, immunosuppression (e.g.
mexthotrexate), comorbidity such as rheumatoid arthritis, smoking, periodontal health.
There are a few guidelines on the management by dentists of patients on
bisphosphonates but these are based on expert opinion and clinician-based
questionnaire surveys rather than scientific evidence. 14 15 If it is possible to predict those
patients at risk and institute preventive or prophylactic measures then the likelihood of
patients developing BRONJ can be minimised.
To date there are no published studies that adequately report incidence of avascular
necrosis specifically BRONJ in a general population. Also although risk factors have been
proposed, previous work has been on selected cohorts. There is a need for a robust
confirmatory study and the national new case registration will allow for a much better
understanding of incidence, risk factors, management and outcome.

Definition of BRONJ

To distinguish avascular necrosis and BRONJ from other delayed healing conditions, the
following working definition of BRONJ has been adapted from that used by the AAOMS
15:

Patients may be considered to have avascular BRONJ if the first two characteristics are
present: 1) exposed or necrotic bone in the maxillofacial region that has persisted for
more than 8 weeks; and 2) no history of radiation therapy to the jaws, and if there is 3)
current or previous treatment with a bisphosphonate, then the patient is considered as
having BRONJ;
It is important to understand that patients at risk for avascular necrosis/BRONJ or with
established avascular necorosis/BRONJ can also present with other common clinical
conditions not to be confused as avascular necorosis/BRONJ. Commonly misdiagnosed
conditions may include, but are not limited to, alveolar osteitis (dry socket), sinusitis,
gingivitis/periodontitis, caries, periapical pathology, and temporomandibular joint
disorders.
For clarification: avascular necorosis/BRONJ can be asymptomatic, associated with pain,
infection, extraoral fistula, jaw fracture.There will be radiographic changes on OPG for
more established cases (ill-defined lytic lesions similar to osteomyelitis extending down
from the surface to the ID canal in the mandible, and even the lower border in advanced
cases). Radiographical assessment is not essential for the diagnosis although normally
accompanies the assessment process. In its early stage the x-ray is normal. OPG is
satisfactory although CT and MR can be used as an adjunct. Biopsy is not necessary to
make the diagnosis.
Who are the principal stakeholders
The project team are working in partnership with;
Faculty of General Dental Practice (FGDP(UK), Royal College of Surgeons of England
British Association of Oral and Maxillofacial Surgeons
British Society of Oral Medicine
Faculty of Dental Surgery, Royal College of Surgeons of England
The British Association of Oral Surgeons
The Association of British Academic Oral and Maxillofacial Surgeons
Which clinicians will be approached and how will they be recruited
Clinicians and departments/units associated with the British Association of Oral and
Maxillofacial Surgeons, British Society of Oral Medicine, the British Association of Oral
Surgeons, and the Association of British Academic Oral and Maxillofacial Surgeons will
be encouraged to register. For example all 154 Oral and Maxillofacial Surgery
departments in England, Wales, Scotland and Northern Ireland have been approached.
A designated clinical lead will be identified and a point of contact established at the
department/unit. In order to be inclusive all other clinicians who are involved in the
management of avascular necrosis/BRONJ will be encouraged to register their cases.
Awareness of the project will be through their parent associations, the Royal College,
national meetings, local audits and journals . As each month there might only be one or
two new cases, the Project Manager will contact the named individual at regular intervals
to ensure that all new patients are being registered. The15 Regional BAOMS Clinical
Effectiveness co-ordinators will also help promote registration in their region.

Which patients will be included
The Oral and Maxillofacial Departments will link with university based Oral Medicine and
Oral Surgery Departments. All new patients presenting with avascular necrosis/BRONJ
will be registered irrespective of age, cause, comorbidity etc. Consent will be sought to
allow contact with the patient in the future for follow-up research.The pilot registration
start on 1st September 2008 in the Mersey Region with full documentation on line planned
from 1st June 2009 to 31st May 2011.
How will the data be collected
Patients will be registered and data entered directly via a webpage designed for the
purpose. The web-based research programme (SPSS Dimensions platform) is sited on
the Royal College of Surgeons web site. The webmaster is Nigel Stripe. Each clinician will
have password-protected access to upload the information requested for each presenting
patient.
The national project will follow a (successful) paper-based pilot in the NW region of
England (September 2008 onwards) and a technical pilot of web-based registration in
May 2009.
Who will collect the data
It is essential to the national new case registration that all cases are identified. To
facilitate this identification the web-based registration process will be quick and simple.
and the link person in each department/unit will ensure the collection of consecutive
cases. Additional data will be more time consuming to enter and each unit is to be
encouraged to make this project part of their ‘audit’ programme. The Regional Clinical
Effectiveness co-ordinators of the Clinical Effectiveness Subcommittee of the British
Association of Oral and Maxillofacial Surgeons will help to encourage unit participation.
Data entry / validation will be assisted by 21 Division Research Coordinators of the
Faculty of General Dental Practice through the DRC network. In cases where clinicians
are uncertain if the patient fulfils the inclusion criteria the steering group will make a
judgement.
How will data entry be monitored
The project manager will have access to the web-tool and at regular time points can
obtain a complete overview as to who has been entering cases and how many and how
complete the record is. In this way a continuous system of monitoring can be ensured
throughout the progress of this study.
What is the dataset to be collected
See data fields / proforma attached as separate document.
How will the tool be piloted
The Project Group has:
• run a pilot of the study on paper, both of case-ascertainment methods and of the data to be collected. Collect qualitative feedback from pilot participants on problems of case-finding and on completing the data proforma. • consider the proforma data received and feedback from the pilot participants • produce a first specification for the web page
Who is included in the project group

Professor Simon Rogers, University Hospital Aintree and Evidence based Practice
Research Centre, Faculty of Health, Edge Hill University, Liverpool.
Role: MFU consultant, Principle investigator and Clinical Lead for BAOMS
Professor Derek Lowe, University Hospital Aintree and Evidence based Practice
Research Centre, Faculty of Health, Edge Hill University, Liverpool
Role: Medical Statistician, Project development, data quality
Dr Nikolaus Palmer PhD BDS MFGDP(UK) General Dental Practitioner, Research
Associate Mersey Deanery, Honorary Lecturer University of Liverpool.
Role: FGDP(UK) member, Project design, Clinical lead for FGDP
Mrs Christine Randall, Senior Medicines Information Pharmacist, North West Medicines
Information Centre.
Role: Project design, data quality
Mrs Amrita Narain, Faculty Research Officer, Faculty of General Dental Practice, Royal
College of Surgeons England.
Role: Day-to day project manager
How will the study be managed
Amrita as the project manager will be the point of daily contact for sites. A central help-
desk will be established as will a study website with FAQs. The project manager will link
directly with the clinical leads and be responsible for preparing materials for project group
meetings, and for managing these meetings including formal minute taking. The project
group will meet regularly (at least 3 monthly) either face-to-face or by virtual means,
throughout the study period to agree protocol, finalise data tools, agree plans for data
analysis, communication plans etc.

Ethics
Ethical approval has been given for the national ‘audit’ via the National Research Ethics
Service (Sefton Research Ethics Committee 08/H1001/179). The Ethics Committee
advised that consent should be sought from the patient around the time of registration not
for the ‘audit’ component but so that it would be possible to contact them should the
opportunity for further research occur in the future. Please see consent form and patient
information sheet.
What is the communication plan for this study
The intention of this case-series is to inform key stakeholders of the workload of cases of
avascular necrosis/BRONJ, potential risk factors and the outcome following treatment.
The findings can then be disseminated to all association members of the stakeholder.
What are the key timelines

Pilot data collection in the Mersey region
Recruit participating hospitals / departments National awareness through stake holders and organisations such as the British Dental Association Website pilot registration Report available of registrations and early follow-up Final report with 1 year follow-up outcomes
Cost of the project –
The project has been supported through:
i.Faculty of the Royal College of General Dental Practice (FGDP(UK) through
Mrs Amrita Narain (day to day project manager)
ii.Royal College of Surgeons Engalnd through Mr Nigel Stripe (web data entry design and
platform)
ii, British Association of Oral and Maxillofacial Surgeons: 7K two years to fund Medical
Statistician
iii. Merck Research Labs: 23K over 4 years (to be agreed) to fund the Principal
Investigator
iv.Myeloma UK: 3K over two years to fund the steering group and associated meetings

References
1.Aapro M, Abrahamsson PA, Body JJ, Coleman RE, Colomer R, Costa L, et al. Guidance on the
Formatted: Italian (Italy)
use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol 2008;19(3):420-32. 2.Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61(9):1115-7. 3.Vieillard MH, Maes JM, Penel G, Facon T, Magro L, Bonneterre J, et al. Thirteen cases of jaw osteonecrosis in patients on bisphosphonate therapy. Joint Bone Spine 2007. 4.Statz TA, Guthmiller JM, Humbert LA, Johnson GK. Intravenous bisphosphonate- associated osteonecrosis of the jaw. J Periodontol 2007;78(11):2203-8. Formatted: Italian (Italy)
5.Ruggiero SL, Drew SJ. Osteonecrosis of the jaws and bisphosphonate therapy. J Dent Res 2007;86(11):1013-21. 6.Garcia Saenz JA, Lopez Tarruella S, Garcia Paredes B, Rodriguez Lajusticia L, Villalobos L, Diaz Rubio E. Osteonecrosis of the jaw as an adverse bisphosphonate event: three cases of bone metastatic prostate cancer patients treated with zoledronic acid. Med Oral Patol Oral Cir Bucal 2007;12(5):E351-6. 7.Yarom N, Yahalom R, Shoshani Y, Hamed W, Regev E, Elad S. Osteonecrosis of the jaw induced by orally administered bisphosphonates: incidence, clinical features, predisposing factors and treatment outcome. Osteoporos Int 2007;18(10):1363-70. 8.Brooks JK, Gilson AJ, Sindler AJ, Ashman SG, Schwartz KG, Nikitakis NG. Osteonecrosis of the jaws associated with use of risedronate: report of 2 new cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103(6):780-6. 9.National Osteoporosis Society. Osteoporosis facts and figures v1.1. 2006. 10.NICE, Techology Appraisal Guidance 87. Bisphosphonates (alendronate, etidronate, risedronate), selective oestrogen receptor modulators (raloxifene) and parathyroid hormone (teriparatide) for the secondary prevention of osteoporotic fragility fractures in postmenopausal women., 2005. 11.Stevenson M LJM, De Nigris E, Brewer N, Davis S, Oakley J. A systematic review and economic evaluation of alendronate, etidronate, risedronate, raloxifene and teriparatide for the prevention and treatment of postmenopausal osteoporosis. Health Technol Assess 2005;9((22)). 12. 7.Jadu F, Lee L, Pharoah M, Reece D, Wang L. A retrospective study assessing theincidence, risk factors and comorbidities of pamidronate-related necrosis of the jaws in multiple myeloma patients. Ann Oncol 2007. 13.Pazianas M, Miller P, Blumentals WA, Bernal M, Kothawala P. A review of the literature on osteonecrosis of the jaw in patients with osteoporosis treated with oral bisphosphonates: prevalence, risk factors, and clinical characteristics. Clin Ther 2007;29(8):1548-58. 14.Dental management of patients receiving oral bisphosphonate therapy: expert panel recommendations. J Am Dent Assoc 2006;137(8):1144-50. 15. American Association of Oral and Maxillofacial Surgeons Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaw-2009 Update.Advisory Task Force on Bisphosphonate-Related Osteonecrosis of the Jaws. 2009.

Source: http://web.rcseng.ac.uk/docs/BONJ%20protocolv2.pdf