Adverse event (AE) reporting of oral clodronate with emphasis on osteonecrosis of the jaw

Abstract

799 Background: Clodronate (CD) is a non-aminobisphosphonate with 18 years of use, representing over 260,000 patient-years. Recent reports describe osteonecrosis or osteomyelitis of the jaw associated with aminobisphosphonates, mainly pamidronate and zoledronic acid. This analysis reviewed spontaneous AE reporting of CD, emphasizing symptoms associated with the jaw. Methods: Schering AG clodronate worldwide database on spontaneous AE reporting and distribution was assessed for serious AE data reported during the marketing history of CD until 30 September 2004. All AE reports were coded using MedDRA (Medical Dictionary for Regulatory Activities). AE reporting rates were estimated using numbers of MedDRA preferred terms against estimated patient exposure for oral formulations. For certain AEs related to bone necrosis or infection, data from clinical trials were analyzed. Results: Overall spontaneous AE reporting rate was 6/10,000 patient-years for oral CD. There were no reports of osteonecrosis, osteomyelitis, or avascular necrosis of the jaw from spontaneous sources or serious AE reports from clinical trials. Two cases of osteomyelitis were reported from clinical trials, one involving the distal fibula associated with placebo of a trial for osteoporosis, the other involving the heel in an adjuvant breast cancer trial that remains blinded as to CD vs placebo arm. In both, osteomyelitis was preceded by local cellulitis and was considered unrelated to study drug. Conclusions: The spontaneous AE reporting rate for oral clodronate use is low. No cases of osteonecrosis of the mandible or maxilla were reported. Reports of osteomyelitis involving other sites appear to be related to factors other than clodronate. Continued safety monitoring and evaluation is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Berlex Laboratories, Schering AG, Schering Oy Schering Oy, Schering AG