ABSTRACT
Title
Assessing the risk of Osteonecrosis of the Jaw (ONJ) due to Bisphosphonates (BP) therapy in the secondary prevention of osteoporotic fractures
Authors
Lapi F 1,2 , Sessa E2, Di Bari M3, Corrao G4, Zambon A4, Scotti L4, Sturkenboom M5,Geppetti P1,6, Gregori D7, Carle F8, Menna A2, Vestri AR9, Vaccheri A10, Piccinni C10, Puccini A10, Montanaro N10, Arcoraci V11, Caputi AP11, Mazzaglia G.2 On behalf of the BEST Study Group
- Department of Preclinical and Clinical Pharmacology, University of Florence, Italy
- Regional Agency for the Healthcare Services of Tuscany, Florence, Italy
- Unit of Gerontology and Geriatrics, Department of Critical Care Medicine and Surgery, University of Florence and Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
- Faculty of Statistical Sciences, University of Milan-Bicocca, Italy
- Departments of Epidemiology & Biostatistics and Medical Informatics, Pharmacoepidemiology Unit, Erasmus University Medical Center, The Netherlands
- Centerof Pharmacoutilization, Pharmacoepidemiology, Pharmacovigilance, and Pharmacoeconomics, University of Florence, Italy
- Department of Environmental Medicine and Public Health, University of Padua, Italy
- Centerof Epidemiology, Biostatistics, and Medical Information Technology, Polytechnic University of Marche, Italy
- University "La Sapienza", Department Of Experimental Medicine and Pathology, Rome, Italy
- Regional Centre for Drug Evaluation and Information (CREVIF), Department of Pharmacology of Bologna, Italy
- Department of Medicine and Pharmacology, University of Messina, Italy
Abstract
Clinical trials indicate that oral BP reduce the incidence of osteoporotic fractures up to 60%. Although the safety of BP appears similar to placebo, adverse reaction reports have suggested an association between BP use and ONJ. On this concern, no epidemiological study including ‘validated’ cases of ONJ has been still conducted.
A case-control study was nested into a cohort of fractured osteoporotic patients. An Adjudication Committee selected codes plausibly related to “true” cases of ONJ according to two levels of contiguity: level I ‘possibly contiguous with ONJ’ (e.g.: 730.08 ‘multiple bone infections, site unspecified’), level II ‘probably contiguous with ONJ’ (e.g.: 526.4 ‘jaw inflammation’). The Incidence Densities (IDs) of overall cases of ONJ and solely for those of level-II contiguity were computed.
Up to 20 controls were matched to each case according to gender, age (±3 years), month and year of the cohort entry. Odds Ratio (OR; 95% Confidence Intervals (CIs)) of being exposed to BPs among cases vs. controls were estimated through conditional logistic regression model. Multivariable analysis includes use of steroids, proton pump inhibitors and diabetes as confounders.
Within a cohort of 73,389 individuals, the ID of ONJ was 0.06 and 0.04 per 10,000 person-years for level-I and level-II criteria, respectively. After the application of exclusion criteria (i.e. previous use of BP, positive history of osteoporotic fractures, Paget and oncologic disease) 104 cases of ONJ (43 level I, 61 level II)were captured among 65,220 eligible participants (mean age: 66.5 yrs; 72.1% females). Among overall cases of ONJ the odds of being exposed to BPs was not different from controls (adjusted OR=1.1; 95% CI: 0.6-1.1). When the analysis was restricted to level-II cases, adjusted OR was 2.8 (95% CI: 1.3-5.9) higher for current users (last prescription within 1 year before the case’s date) of BP than never users.
Incidence Density of ONJ was coherent with literature (Mavrokokki et al., 2007) when it was computed for level-II codes. These findings seem to suggest an association between use of oral BP and ONJ. Further analyses on definitively validated cases are needed.
Mavrokokki et al., (2007). J Oral Maxillofac Surg. 65:415-2.
A case-control study was nested into a cohort of fractured osteoporotic patients. An Adjudication Committee selected codes plausibly related to “true” cases of ONJ according to two levels of contiguity: level I ‘possibly contiguous with ONJ’ (e.g.: 730.08 ‘multiple bone infections, site unspecified’), level II ‘probably contiguous with ONJ’ (e.g.: 526.4 ‘jaw inflammation’). The Incidence Densities (IDs) of overall cases of ONJ and solely for those of level-II contiguity were computed.
Up to 20 controls were matched to each case according to gender, age (±3 years), month and year of the cohort entry. Odds Ratio (OR; 95% Confidence Intervals (CIs)) of being exposed to BPs among cases vs. controls were estimated through conditional logistic regression model. Multivariable analysis includes use of steroids, proton pump inhibitors and diabetes as confounders.
Within a cohort of 73,389 individuals, the ID of ONJ was 0.06 and 0.04 per 10,000 person-years for level-I and level-II criteria, respectively. After the application of exclusion criteria (i.e. previous use of BP, positive history of osteoporotic fractures, Paget and oncologic disease) 104 cases of ONJ (43 level I, 61 level II)were captured among 65,220 eligible participants (mean age: 66.5 yrs; 72.1% females). Among overall cases of ONJ the odds of being exposed to BPs was not different from controls (adjusted OR=1.1; 95% CI: 0.6-1.1). When the analysis was restricted to level-II cases, adjusted OR was 2.8 (95% CI: 1.3-5.9) higher for current users (last prescription within 1 year before the case’s date) of BP than never users.
Incidence Density of ONJ was coherent with literature (Mavrokokki et al., 2007) when it was computed for level-II codes. These findings seem to suggest an association between use of oral BP and ONJ. Further analyses on definitively validated cases are needed.
Mavrokokki et al., (2007). J Oral Maxillofac Surg. 65:415-2.