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

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.

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.

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

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

 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 

WHENCODED WITH

Case definition

Hospital procedure code billing for surgery to jaw or oral cavity

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 5,2925.67 (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.

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

 

 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=0.41MPR , alendronate   <50%   50-80% 2.76 (1.32-5.80) p=0.007 >80% 2.11 (1.16-3.82) p=0.014Dose years of alendronate   <5  5-10 2.20 (1.11-4.34) p=0.023≥ 10 2.25 (0.47-10.70) p= 0.31Comorbid conditions and comedications

 

Diabetes 3.79 (1.81-7.95) p<0.001Rheumatoid disorders 2.10 (1.21-3.65)p=0.009Chronic pulmonary disease 1.96 (1.10-3.48) p=0.02PPI in last year 3.17 (1.90-5.29) p<0.001Chronic kidney disease 1.51 (0.24-9.54) p=0.66Dementia 1.82 (0.57-5.78) p=0.32Ulcer disease 1.07 (0.53-2.16) p=0.86Major osteoporotic fracture 1.23 (0.75-2.00) p=0.41Fractures, other 0.83 (0.44-1.59) p=0.58Prednisolone in last year 1.18 (0.65-2.45) p=0.58

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

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