Bo Abrahamsen's presentation from Osteoporosis 2016: Surgically treated osteonecrosis and osteomyelitis of the jaw and oral cavity in patients highly adherent to alendronate treatment. Find out more at: https://nos.org.uk/conference

1. SURGICALLY TREATED OSTEONECROSIS AND
OSTEOMYELITIS OF THE JAW AND ORAL
CAVITY IN PATIENTS HIGHLY ADHERENT TO
ALENDRONATE TREATMENT
Bo Abrahamsen, Pia A Eiken, Daniel Prieto-Alhambra, Richard Eastell
University of Southern Denmark, Odense, Denmark.Holbæk Hospital, Holbæk, Denmark.
Hillerød Hospital, Hillerød, Denmark University of Copenhagen, Copenhagen, Denmark.
Musculoskeletal Pharmaco- and Device Epidemiology, NDORMS, University of Oxford, Oxford,UK.
IMIM-Parc de Salut Mar and RETICEF, Universitat Autònoma de Barcelona and Instituto Carlos III Barcelona, Spain.
University of Sheffield, Sheffield, UK

2. Disclosures
 Institutional research contracts and grants
 UCB
 Novartis
 Other
 International Osteoporosis Foundation, Committee of Scientific Advisors
 American Society for Bone and Mineral Research, Board of Directors
 Journal of Bone and Mineral Research, Associate Editor
 This study received no external funding.

3.  Osteonecrosis of the jaw (ONJ) is regarded as
a rare event in users of oral bisphosphonates
whereas it is a common adverse event in an
oncology setting where dose intensity is higher
and the route is intravenous.
 Clinical diagnosis based on exposed bone for
more than 8 weeks observed by a health
professional.
 No clear indication from past studies that the risk
of ONJ increases with increasing treatment time
for oral bisphosphonates.
Background
Solomon, DH et al Osteoporosis International 2013,24 (1):237–44.

4.  The study used Danish national health registers covering all
residents in the country.
 The National Prescription Database was used to identify incident
users of alendronate between 1.1.1996 and 31.1.2007.
(N=61,990) aged 50-94.
 In- and outpatient hospital billing codes were followed until
31.12.2013 for surgery to the oral cavity or jaws using the Danish
National Hospital Discharge Register. The indication for surgery was
identified from ICD-10 codes coded on the same hospital contact.
Methods and study population

5.  The study used Danish national health registers covering all
residents in the country.
 The National Prescription Database was used to identify incident
users of alendronate between 1.1.1996 and 31.1.2007:
(N=61,990) aged 50-94.
 In- and outpatient hospital billing codes were followed until
31.12.2013 for surgery to the oral cavity or jaws using the Danish
National Hospital Discharge Register. The indication for surgery was
identified from ICD-10 codes coded on the same hospital contact.
 The first step of the analysis focused by highly adherent alendronate
use by truncating the study period for life tables and Cox analyses at
death, end of study or failing refill adherence (<80% MPR).
 Second, a nested case-control design was employed irrespective of
level of adherence to compare the influence of dose years, recency
of use and refill compliance on risk.
Methods and study population

6. ICD-10 code indicating
inflammatory conditions of the jaw
or oral cavity, excluding
osteoradionecrosis: K102, K102B,
K102C, K102D, K102G, K102I,
K102J
ICD-10 code indicating
osteonecrosis or osteomyelitis at
any anatomical location:
M861, M862, M864, M866, M868,
M869C, M870, M871, M873, M878,
M879
WHEN
CODED
WITH
Case definition
Hospital procedure
code billing for
surgery to jaw or oral
cavity

7. Duration of highly adherent
alendronate exposure, years
Persons
with
events
Patient
years at
risk
Rate per 10,000
patient years
Before start (last 12mo) 7 61,990 1.13 (0.45-2.33)
0-5 77 194,445 3.96 (3.13-4.95)
5 to 10 27 56,269 4.80 (3.16-6.98)
10+ 3 5,292 5.67 (1.17-16.57)
Duration of use and surgery rate
Rate (with 95% CI) of surgically treated osteomyelitis or osteonecrosis of the jaw or
oral cavity as a function of duration of highly adherent alendronate use
(MPR>80%).
≈ “Noise rate”
A total of 107 alendronate exposed patients received surgery.

8.  Strongest predictors of surgically treated
osteonecrosis/osteomyelitis of the jaw/oral cavity in
highly adherent users:
 Rheumatic disorders (OR 1.75, 95% CI 1.14-2.69).
 Chronic lung diseases (OR 1.78, 1.14-2.77).
 Diabetes (OR 2.32, 1.21-4.43).
 Prednisolone use (OR 1.72, 1.11-2.66).
 Ulcer disease (OR 1.85, 1.02-3.36).
Risk factors

9. Adjusted OR
(107 cases and
534 control subjects)
User status , alendronate
Past user (≥ 1 year before)
Recent user (< 1y before) 4.00 (1.90-8.40) p<0.001
Current user (< 3 mo) 1.29 (0.70-2.37) p=0.41
MPR , alendronate
<50%
50-80% 2.76 (1.32-5.80) p=0.007
>80% 2.11 (1.16-3.82) p=0.014
Dose years of alendronate
<5
5-10 2.20 (1.11-4.34) p=0.023
≥ 10 2.25 (0.47-10.70) p= 0.31
Comorbid conditions and comedications
Diabetes 3.79 (1.81-7.95) p<0.001
Rheumatoid disorders 2.10 (1.21-3.65)p=0.009
Chronic pulmonary disease 1.96 (1.10-3.48) p=0.02
PPI in last year 3.17 (1.90-5.29) p<0.001
Chronic kidney disease 1.51 (0.24-9.54) p=0.66
Dementia 1.82 (0.57-5.78) p=0.32
Ulcer disease 1.07 (0.53-2.16) p=0.86
Major osteoporotic fracture 1.23 (0.75-2.00) p=0.41
Fractures, other 0.83 (0.44-1.59) p=0.58
Prednisolone in last year 1.18 (0.65-2.45) p=0.58

10.  The absolute rate of surgically treated osteomyelitis
and osteonecrosis of the jaw or oral cavity is low, ~5
per 10,000 patient years, even in longer term (5-10
years) adherent (MPR>80%) users of alendronate.
 Risk factors include conditions that directly or
indirectly influence the oral mucosa (diabetes,
conditions associated with oral or inhaled
glucocorticoid use). Also importance of PPI use /
ulcer disease.
 Confounder adjusted analyses indicate that risk are
significantly higher after 5+ years of use and that
risks are higher in users with high adherence.
Key findings

11.  Milder stages of ONJ are treated conservatively
and the events tracked in this study likely
represent more advanced osteonecrosis and
osteomyelitis that could compare with major
osteoporotic fractures in morbidity.
Limitations